Materiały źródłowe

• #1 Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6650620/

  Currently, 47 million people live with dementia globally, and it is estimated to increase more than threefold (~131 million) by 2050. Alzheimers disease (AD) is one of the major causative factors to induce progressive dementia. AD is a neurodegenerative disease, and its pathogenesis has been attributed to extracellular aggregates of amyloid (A) plaques and intracellular neurofibrillary tangles made of hyperphosphorylated -protein in cortical and limbic areas of the human brain. […] The anomalous processing of APP by -secretases and -secretases leads to production of A40 and A42 monomers, which further oligomerize and aggregate into senile plaques. […] AD is a highly complex and progressive neurodegenerative disease. It is one of the leading cause of dementia cases globally. […] Reported histopathological characteristics of AD are extracellular aggregates of A plaques and intracellular aggregations of neurofibrillary tangles (NFTs), composed of hyperphosphorylated microtubule-associated .

• #1 Alzheimer’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Alzheimer%27s_disease

  Alzheimer’s disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. The causes of Alzheimer’s disease remain poorly understood. The progression of the disease is largely characterised by the accumulation of malformed protein deposits in the cerebral cortex, called amyloid plaques and neurofibrillary tangles. These misfolded protein aggregates interfere with normal cell function, and over time lead to irreversible degeneration of neurons and loss of synaptic connections in the brain. Alzheimer’s disease is believed to occur when abnormal amounts of amyloid beta (A), accumulating extracellularly as amyloid plaques and tau proteins, or intracellularly as neurofibrillary tangles, form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function. The most predominant hypothesis is the amyloid beta (A) hypothesis. Alzheimer’s disease has been identified as a protein misfolding disease, a proteopathy, caused by the accumulation of abnormally folded amyloid beta protein into amyloid plaques, and tau protein into neurofibrillary tangles in the brain. The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau as paired helical filaments. Eventually, they form neurofibrillary tangles inside neurons. Evidence supports A as playing a central role in the pathogenesis of AD, but it does not completely explain the condition, as individuals may have normal cognition and very high A burden in their brains at an advanced age. Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer’s disease. Microglia are topographically associated with pTau and A within the brain, even when each pathologic component occurs in distinct brain regions, and microglial activation has been documented in those with mild cognitive impairment, suggesting that microglial dysfunction may precede plaque deposition as an inciting event in AD.

• #1 Mechanisms of Alzheimer’s Disease Pathogenesis and Prevention: The Brain, Neural Pathology, N-methyl-D-aspartate Receptors, Tau Protein and Other Risk Factors

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5290713/

  The characteristic features of Alzheimers disease (AD) are the appearance of extracellular amyloid-beta (A) plaques and neurofibrillary tangles in the intracellular environment, neuronal death and the loss of synapses, all of which contribute to cognitive decline in a progressive manner. […] A number of hypotheses have been proposed that may explain AD pathogenesis: (a) the A-amyloid hypothesis, (b) the A-amyloid oligomer hypothesis, (c) the presenilin hypothesis, (d) the Ca2+ dysregulation hypothesis, (e) the lysosome hypothesis, and (f) the tau hypothesis. […] A is the most widely studied component of AD pathogenesis. The amyloid hypothesis broadly posits that excessive amounts of A peptide in the brain (particularly A42) are responsible for AD-related pathology, including amyloid plaques, neurofibrillary tangles, synapse loss, and eventual neuronal cell death.

• #1 Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-01911-3

  Alzheimers disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate and diverse, stemming from a combination of factors such as aging, genetics, and environment. Our current understanding of AD pathologies involves various hypotheses, such as the cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, and abnormal autophagy. Nonetheless, unraveling the interplay among these pathological aspects and pinpointing the primary initiators of AD require further elucidation and validation. […] The etiology of AD is complex and diverse, and the precise mechanisms underlying its onset are not yet completely understood. Beyond the pivotal role of A and tau, a spectrum of other factors may contribute to the pathology of AD, such as acetylcholine deficiency, neuroinflammation, oxidative stress, biometal dyshomeostasis, glutamate imbalance, insulin resistance, gut microbiome abnormalities, cholesterol homeostasis disruption, mitochondrial dysfunction, and autophagy abnormalities.

• #1 Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6650620/

  A plaques develop initially in basal, temporal, and orbitofrontal neocortex regions of the brain and in later stages progress throughout the neocortex, hippocampus, amygdala, diencephalon, and basal ganglia. […] Amyloid pathogenesis starts with altered cleavage of amyloid precursor protein (APP), an integral protein on the plasma membrane, by -secretases (BACE1) and -secretases to produce insoluble A fibrils. […] This polymerization leads to activation of kinases, which leads to hyperphosphorylation of the microtubule-associated protein, and its polymerization into insoluble NFTs. […] The aggregation of plaques and tangles is followed by microglia recruitment surrounding plaques. This promotes microglial activation and local inflammatory response, and contributes to neurotoxicity. […] AD is also characterized by the presence of NFTs. These tangles are the result of hyperphosphorylation of the microtubule-associated protein.

• #1 Pathophysiology of dementia

  https://www1.racgp.org.au/ajgp/2023/august/pathophysiology-of-dementia

  The pathophysiology of dementia is broadly thought to be related to the aggregation and accumulation of misfolded proteins (termed proteinopathies) and/or associated with cerebrovascular disease (CVD). The most common cause of late-onset dementia is AD, followed by dementia with Lewy bodies (DLB), vascular dementia and frontotemporal dementia (FTD). […] The pathological hallmarks of AD are the accumulation of extracellular amyloid-b (A) plaques and intraneuronal neurofibrillary tangles. […] The amyloid cascade hypothesis, first described in 1992, suggested that the accumulation of A plaques was driven by an imbalance between the A production (by cleavage of amyloid precursor protein [APP] by – and -secretase) and A clearance. […] The strongest evidence for the role of A pathology in AD came from studies of individuals with dominantly inherited AD, in whom mutations in one of three different genes (APP, presenilin 1 [PSEN1], presenilin 2 [PSEN2]) led to the overproduction and aggregation of A, with subsequent development of AD at an early age (~30-50 years).

• #1 Alzheimer’s disease: amyloid-based pathogenesis and potential therapies

  https://www.cell-stress.com/researcharticles/alzheimers-disease-amyloid-based-pathogenesis-and-potential-therapies/

  It is now generally agreed that the soluble A oligomers, rather than amyloid plaques, are synaptotoxic. […] Although the accumulation of A is acknowledged as a key factor in the cognitive deficit observed in AD patients, other studies have pointed out the weakness of the original amyloid cascade hypothesis and pointed out some challenges. […] The fact that various A species are produced has a pathogenic impact on neurons, and the longer A42 is believed to be more toxic than A40. […] A peptide plays an important role in AD by influencing synapses and, in turn, neural circuits. Accumulation of A in the brain parenchyma can lead to loss of dendritic spines and synapses as well as alterations in synaptic transmission and neural activity. […] A high level of A leads to aberrant neuronal activity by enhancing synchrony among the remaining glutamatergic synapses.

• #1 Insights into Alzheimer disease pathogenesis from studies in transgenic animal models | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-insights-into-alzheimer-disease-pathogenesis-S1807593222015836

  There is now a great interest in identifying which A species (A1-40, A1-42, or truncated A) and form (oligomers or deposits) would be responsible for neurotoxicity, and in understanding the relationship between A and Tau pathologies. […] These studies indicate that intraneuronal soluble A is a pathological feature of AD that has long been neglected and is turning out to be the key factor leading to neuronal loss in the disease before the extracellular A deposition. […] Loss of neuronal synaptic density and synapse number represents another invariant feature of AD that appears to precede overt neuronal degeneration. […] There is accumulating evidence from AD transgenic mice that intraneuronal A1-42 triggers not only early neuronal loss but also synaptic deficits. […] Studies in a transgenic animal model of AD that exhibits marked neuronal and synaptic loss indicate that alterations in synaptic integrity precede neuronal loss, which is in accordance with the hypothesis that synaptic loss is one of the earliest events in AD pathogenesis. […] Finally, the AD transgenic models may allow to define and evaluate potential drug targets and to develop therapeutic strategies that might interfere or delay the onset of AD.

• #1 Mechanisms of Alzheimer’s Disease Pathogenesis and Prevention: The Brain, Neural Pathology, N-methyl-D-aspartate Receptors, Tau Protein and Other Risk Factors

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5290713/

  Excitotoxicity occurs as a result of the chronic, moderate activation of NMDA receptors, leading to neurodegeneration. […] The excitotoxicity hypothesis is supported by clinical evidence indicating that the NMDA receptor antagonist memantine slows AD progression. […] NMDA receptors mediate synaptic plasticity, critical for memory and learning functions, through long-term potentiation (LTP). […] Several recent studies have examined the relationship between A and NMDA. […] A-induced spine loss is associated with a decrease in glutamate receptors, also required for LTD, in a calcineurin-dependent manner. […] The accumulation of the protein tau within the brain tissue of AD patients was first described in 1986. […] Tau phosphorylation was also proposed as a potential contributor to the formation of neurofibrillary tangles in AD. […] Hyperphosphorylated tau thus has an important role in intracellular neurofibrillary changes and the pathogenesis of AD and related tauopathies.

• #1 Pathophysiology of dementia

  https://www1.racgp.org.au/ajgp/2023/august/pathophysiology-of-dementia

  Neurofibrillary tangles formed by phosphorylated (p-) tau proteins are one of the cardinal features of AD. Tau hyperphosphorylation causing microtubule destabilisation is generally thought to be the main pathological process driving downstream neurodegenerative damage resulting in microglial activation, synaptic loss and neuronal death. […] In AD, according to the Braak system, tau pathology typically originates in the temporal cortices and tau, rather than A, has been shown to be the main determinant of brain atrophy, cognitive changes and clinical decline in patients. […] The amyloid cascade hypothesis has remained the main pathological model in AD for decades; however, there is increasing evidence that supports multicausality of the pathophysiology of AD. […] In addition to A and tau, coexisting neuropathologies are commonly detected in individuals with AD.

• #1 Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-020-00391-7

  Tau aggregates can induce mitochondria fragmentation, impair synaptic vesicle mobility and release, thereby leading to presynaptic dysfunction. […] In addition, pathological tau species can activate microglial NF-B and NLRP3 inflammasome pathways, leading to pro-inflammatory cytokine release. […] Together, these results suggest that synaptogyrin-3 is a key modulator for tau-induced presynaptic dysfunction.

• #1 Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-01911-3

  Numerous hypotheses have been proposed to unravel the pathogenesis of AD, yet a unified theory remains elusive, likely due to the complex nature of AD. AD can be categorized into two main types: familial (accounting for 1-5% of AD cases) and sporadic forms (over 95% of cases). Familial AD (FAD) is predominantly characterized by autosomal dominant genetic mutations in amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes, typically manifesting between 30-65 years and progressing rapidly. In contrast, sporadic AD (SAD), also known as late-onset AD, usually manifests after the age of 65 and is influenced by a combination of genetic risks, environmental factors, and various comorbidities. […] The cholinergic hypothesis was the earliest to delineate the pathogenesis of AD. It describes the severe damage of cholinergic neurons in the nucleus basalis of meynert (NBM), leading to a marked decrease in choline acetyltransferase (ChAT) activity within the primary projection areas – the cerebral cortex and hippocampus (regions associated with learning and memory).

• #1 Pathophysiology of dementia

  https://www1.racgp.org.au/ajgp/2023/august/pathophysiology-of-dementia

  CVD and AD share many vascular risk factors and often coexist in older people with dementia. […] Neuroinflammation with microglial activation has been increasingly recognised to play an important role in the pathogenesis of AD and is involved in A deposition, neuronal damage and cell death. […] Cholinergic transmission, implicated in modulating cognitive processes such as learning, memory and arousal, also plays an integral part in AD.

• #1 Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-020-00391-7

  Alzheimers disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. […] Studies within the last few decades provide growing evidence for a central role of amyloid (A) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis. […] We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota. […] Primary pathological hallmarks of AD include A plaques, neurofibrillary tangles (NFTs), gliosis, and neuronal loss, accompanied by cerebrovascular amyloidosis, inflammation and major synaptic changes. […] The extracellular domain of APP mediates cell-to-cell adhesion to support synaptic connections.

• #1 Alzheimer’s Disease; Mechanism, Mutations, and Applications of Nano-Medicine

  https://www.imrpress.com/journal/FBL/28/10/10.31083/j.fbl2810258/htm

  The complex of γ-secretase, which consists of a membrane-embedded protease known as presenilin 1 (PSEN1), presenilin enhance 2 (Pen-2), Aph-1, and Nicastrin, goes on to cleave C99, which is then involved in many essential cellular processes. […] PSENs are well-known for their pleiotropic γ-secretase-independent functions in addition to their well-described catalytic activity within the γ-secretase complex, particularly in maintaining Ca2+ homeostasis but also in protein trafficking, cell adhesion, and autophagy.

• #1 The Amyloid-β Pathway in Alzheimer’s Disease | Molecular Psychiatry

  https://www.nature.com/articles/s41380-021-01249-0

  In addition, brain A accumulation appears to be upstream to other pathomechanistic alterations of the biological continuum of AD, including the spreading of NTFs, and involvement of neuronal and synaptic loss. […] The temporal and spatial evolution of these pathophysiological alterations underlies AD cognitive and functional decline across a clinical continuum, from preclinical to prodromal and dementia stages. […] The potential pathogenic role of the APP gene in humans is supported by the existence of a rare protective variant APP A673T (or A2T) next to the APP -secretase site that reduces both APP cleavage and the production of amyloidogenic A peptides. […] The A is a 4kDa fragment of the amyloid precursor protein (APP), a larger precursor molecule widely produced by brain neurons, vascular and blood cells (including platelets), and, to a lesser extent, astrocytes.

• #1 Alzheimer’s Disease; Mechanism, Mutations, and Applications of Nano-Medicine

  https://www.imrpress.com/journal/FBL/28/10/10.31083/j.fbl2810258/htm

  The deficiency of some neurotransmitters (like acetylcholine, dopamine, and serotonin) and an imbalance among these neurotransmitters are the root causes of the cognitive impairments linked to Alzheimer’s disease (AD). […] However, loss of synapses and axonal damage are probably crucial neuropathological elements that cause dementia. […] The processing of APP may change as a result of mutations around the cleavage site of α-secretase, which may increase the Aβ peptide’s proteolytic resistance. […] The APP gene is duplicated due to the triplication of chromosome 21, which may improve APP expression and Aβ buildup. […] These results imply that AD pathogenesis may be connected to APP overexpression. […] The endosomal/lysosomal and β-secretase cleavages of Aβ are susceptible to N-terminal alterations in the Aβ sequence.

• #1 Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-020-00391-7

  APP deficiency increases KCC2 degradation via tyrosine-phosphorylation and ubiquitination, therefore, leading to GABA reversal potential depolarization and impairment during GABAA receptor-mediated inhibition. […] The amyloidogenic pathway comprises sequential proteolytic cleavage of APP by -secretase and the -secretase complex. […] Therefore, A42 is thought to be a key player in initiating plaque formation and AD pathogenesis. […] Dysregulated APP processing may contribute to AD pathogenesis by elevating A production, and reducing the A40/42 ratio. […] Tau is a microtubule-binding protein, which can undergo various types of post-translational modifications (PTMs), such as phosphorylation and truncation. […] Aberrant PTMs induces tau dissociation from microtubules, leading to tau aggregation and oligomer formation.

• #1 Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6650620/

  GSK3 and CDK5 are the kinases primarily responsible for phosphorylation of . […] Abnormal processing of APP leads to secretion of A, which affects GSK3 kinases, leading phosphorylation of the protein. This leads to aggregation of filaments that are insoluble and finally formation of huge masses of NFTs in neurons. […] In addition to extracellular A plaques and NFTs due to hyperphosphorylation, microglial infiltration in response to these aggregates exacerbates AD pathogenesis. […] A rare mutation of TREM2 (R47H) has been reported that plays a potent role in aggravating the risk of developing AD. […] Understanding all these factors and then designing therapeutics specific to targeting them is the need of the hour.

• #1 A Newly Identified Mechanism of Microglia in Alzheimer’s Disease Opens Doors to New Treatment Targets

  https://reports.mountsinai.org/article/neuro2024-03-microglia-alzheimers-disease-yue-choi

  Scientists at the Icahn School of Medicine at Mount Sinai uncovered a previously unrecognized role of microglia autophagy and senescence in Alzheimers disease pathology. […] Research has established that microglia employ autophagy when responding to amyloid plaques in brains affected by Alzheimers disease. […] This new study connects the dots between autophagy and microglia. […] We believe autophagy plays a very important role in sustaining the disease-associated microglia, allowing them to engage the plaques and prevent them from poisoning neighboring cells. […] When disease-associated microglia become senescent, they lose their neuroprotective function, the study showed. […] His study showed that autophagy-deficient microglia failed to engage with beta-amyloid plaques to keep them contained.

• #1 Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-01911-3

  During regular metabolic processes, the body produces reactive oxygen species (ROS), reactive nitrogen species, and other highly reactive and unstable substances. […] In physiological conditions, trace metals maintain homeostasis of the neuronal metal ion microenvironment. […] Glutamate is the main excitatory neurotransmitter of glutamatergic neurotransmission in the CNS. […] The microbiota-gut-brain axis hypothesis has attracted significant attention, unveiling potential pathways for novel therapeutic strategies. […] Autophagy, a highly conserved metabolic degradation process, maintains cellular homeostasis by delivering intracellular protein aggregates and damaged organelles to lysosomes for degradation and recycling. […] Several pathological factors in AD, such as A, pro-inflammatory cytokines, and oxidative stress, activate microglia and initiate downstream signaling pathways such as MAPK, NF-B, and PI3K/Akt.

• #1 Pathophysiology and management of alzheimer’s disease: an overview – MedCrave online

  https://medcraveonline.com/JAPLR/pathophysiology-and-management-of-alzheimerrsquos-disease-an-overview.html

  Studies have shown that mitochondrial dysfunction plays an important role in AD, in which oxidative stress-induced respiratory chain dysfunction, loss of mitochondrial biogenesis, defects of mitochondrial dynamics and mtDNA mutations are observed. […] Current treatments for AD are not directly targeted to mitochondria. […] The comprehensive management of AD entails both nonpharmacological and pharmacologic interventions. […] Current pharmacological treatments of AD reduce symptoms without affecting the main pathological characteristics of the disease. […] New therapeutic approaches, including those more closely targeted to the pathogenesis of the disease are under research. […] The association of immune proteins and immune-competent microglial cells with senile plaques (SP) in both AD and normal aging suggests that these drugs may be able to modify the course of Alzheimers disease, either by interfering with Senile Plaques formation or by suppressing the inflammation associated with the Senile Plaques.

• #1 An Insight into Cellular and Molecular Mechanisms Underlying the Pathogenesis of Neurodegeneration in Alzheimer’s Disease

  https://www.mdpi.com/2227-9059/11/5/1398

  An Insight into Cellular and Molecular Mechanisms Underlying the Pathogenesis of Neurodegeneration in Alzheimer’s Disease […] Alzheimer’s disease (AD) is the most prominent neurodegenerative disorder in the aging population. It is characterized by cognitive decline, gradual neurodegeneration, and the development of amyloid-β (Aβ)-plaques and neurofibrillary tangles, which constitute hyperphosphorylated tau. […] Emerging evidence over the past few decades supports the critical role of Aβ and tau in AD pathogenesis and the participation of glial cells in different molecular and cellular pathways. This review extensively discusses the current understanding concerning Aβ- and tau-associated molecular mechanisms and glial dysfunction in AD. […] The neurodegenerative disorder called Alzheimer’s disease mainly proceeds from brain cell degeneration, and ultimately leads to demise following dementia. […] Two distinct types of aggregates are the primary neuropathological indicators of AD. The first is an extracellular amyloid (Aβ) peptide deposit (plaques). The second is hyperphosphorylated Tau protein fibrillary aggregation (tangles). It is typically proposed that neuroinflammation is another pathogenic characteristic of AD. […] Normal aging allows the brain to shrink somewhat, yet oddly enough, a considerable proportion of neurons are not lost. Unfortunately, in the case of AD, many neurons stop functioning, break connectivity with the surrounding neurons, and ultimately die, causing significant harm. […] The symptoms of AD change with the phases of the disease. AD is categorized into three stages: preclinical or pre-symptomatic, mild, and dementia-stage, depending on the extent of cognitive deterioration. […] For over three decades, the amyloid hypothesis has been the dominant and most widely accepted mechanistic theory of how AD develops. According to their theory, the accumulation of oligomeric Aβ (oAβ)-peptides are responsible for the pathophysiology causing downstream events such as neuroinflammation, the formation of neurofibrillary tangles (NFT), and vascular injury, encouraging dementia and cognitive deficits. […] The primary element that significantly contributes to the pathophysiology of AD and is often regarded as the principal reason for AD development is the amyloid β peptide. […] Tau is a cytosol protein mostly available in axons and is a neuronal microtubule-associated protein. […] The presence of Aβ, neural inflammation, enzymes, and oxidative stress that modulate phosphatases and kinases can all impact the phosphorylated tau-protein conformation. […] The formation of Tau into neurofibrillary tangles is in close alliance with the neurodegeneration (i.e., neural demise) and brain atrophy seen in AD. […] According to multiple evidence-based studies, the pathophysiology of AD may be influenced by mitochondrial dysfunction. […] The idea that oxidative stress might be what causes AD pathogenesis triggered by Aβ is supported by the finding that oxidative stress emerges earlier in AD. […] Nitrosative stress arises when various defensive mechanisms fail to balance the formation of reactive nitrogen species (RNS), which harms intracellular constituents. […] Multiple evidence-based findings imply that ROS might be crucial in the emergence of neurodegeneration in AD. […] DNA is nucleic acid found in the mitochondria (mtDNA) and nuclear (nDNA) material of living cells. […] Another characteristic of AD is neuroinflammation, which appears as gliosis and is marked by the activation and proliferation of the two main glial cell types in the brain, astrocytes and microglia. […] In AD, inappropriate Aβ collection seems to be what starts the inflammatory processes. […] Considering that several tau transgenic animal models and tauopathy sufferers exhibit gliosis even in the absence of Aβ pathology, pathogenic tau species can also activate microglia and astrocytes. […] By eliminating proteins that are inappropriately folded or clumped together, the ubiquitin-proteasome pathway (UPP) helps to maintain cellular integrity. […] In the case of neuroinflammation, serum and brain specimens from AD patients include inflammatory mediators such TNF-α, IL-6, IL-β, and cyclooxygenase-2 (COX-2).

• #1 Pathogenesis of Alzheimer’s Disease

  https://www.mdpi.com/1422-0067/24/1/107

  Alzheimer’s disease (AD) is the most common type of dementia, accounting for 60% to 80% of all cases. It is estimated that this debilitating neurodegenerative disorder currently affects 50 million patients worldwide and indirectly impacts the lives of tens of millions who deal with many years of cognitive decline in their loved ones. A small percentage of all AD cases are linked to dominant genetic mutations in three genes codifying for APP (amyloid precursor protein), PSEN1 (presenilin 1), and PSEN2 (presenilin 2) and are typically associated with early-onset forms of the disease in which clinical symptoms appear before the age of 65. The majority of the patients exhibit late-onset Alzheimer’s disease (LOAD), which appears later in life and is sporadic in nature. Although in these cases the disease is not hereditary and shows no single genetic cause, current evidence supports the existence of a number of genetic risk factors, among which the presence of the E4 allele in the ApoE (apolipoprotein E) gene—occurring in about 16% of the population—is the most significant. Lifestyle behaviors such as poor diet and reduced physical activity, as well as environmental and metabolic risk factors including diabetes, cerebrovascular disease, head injury, and stress, are typically linked with an increased risk for the disease.

• #1 The Complex Pathogenesis and Genetics of Alzheimer’s Disease | MedPage Today

  https://www.medpagetoday.com/medical-journeys/alzheimers-disease/111933

  After a long debate, a working group convened by the Alzheimer’s Disease Sequencing Project came to consensus that the APOE4 gene is definitively toxic. […] A single inherited copy of the APOE4 allele increases Alzheimer’s risk approximately three- to four-fold, while two inherited copies increase risk by some 12-fold. […] The genetic alterations of Down syndrome also mean elevated risk for Alzheimer’s disease. […] Autosomal dominant Alzheimer’s disease accounts for only a small percentage of cases (5-10%) but results in disease for nearly all who inherit mutations in one of three genes: […] All three are strongly associated with early-onset forms of the disease, with clinical symptoms appearing before age 65.

• #1 Alzheimer’s disease – the journey of a healthy brain into organ failure | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-022-00523-1

  Both autopsy and imaging studies show that APOE4 leads to earlier onset of A deposition and typically results in higher levels of A deposited, whereas APOE2 delays onset of deposition. […] This difference translates into the clinical setting where APOE4 carriers typically show increased incidence of AD and an early onset of symptoms compared to those with APOE3 alleles whereas APOE2 carriers show reduced incidence of AD and delayed onset. […] Thus, it is plausible that plaque formation is an acutely adaptive response that is initially protective but over time turns toxic. […] There is compelling data from model systems that select EOAD-linked APP and PSEN mutant may alter cellular functions such as endosomal, autophagic and lysosomal trafficking. […] However, we still have little definitive insight into both the how and when regarding the role of immune systems in mediating AD pathophysiology.

• #1 Amyloid-Independent Mechanisms in Alzheimer’s Disease Pathogenesis | Journal of Neuroscience

  https://www.jneurosci.org/content/30/45/14946

  Despite the progress of the past two decades, the cause of Alzheimer’s disease (AD) and effective treatments against it remain elusive. The hypothesis that amyloid- (A) peptides are the primary causative agents of AD retains significant support among researchers. Nonetheless, a growing body of evidence shows that A peptides are unlikely to be the sole factor in AD etiology. Evidence that A/amyloid-independent factors, including the actions of AD-related genes, also contribute significantly to AD pathogenesis was presented in a symposium at the 2010 Annual Meeting of the Society for Neuroscience. Here we summarize the studies showing how amyloid-independent mechanisms cause defective endo-lysosomal trafficking, altered intracellular signaling cascades, or impaired neurotransmitter release and contribute to synaptic dysfunction and/or neurodegeneration, leading to dementia in AD. A view of AD pathogenesis that encompasses both the amyloid-dependent and -independent mechanisms will help fill the gaps in our knowledge and reconcile the findings that cannot be explained solely by the amyloid hypothesis.

• #1 Amyloid-Independent Mechanisms in Alzheimer’s Disease Pathogenesis | Journal of Neuroscience

  https://www.jneurosci.org/content/30/45/14946

  Despite the genetic and cell biological evidence that supports the amyloid hypothesis, it is becoming clear that AD etiology is complex and that A alone is unable to account for all aspects of AD (Pimplikar, 2009). […] The fact that vast overproduction of A peptides in the mouse brain failed to cause neurodegeneration raises further questions as to whether accumulation of A peptides is indeed the culprit for neurodegeneration in AD. […] This article highlights the findings that were presented in a symposium and is not meant to be a comprehensive review of AD pathogenesis. Here we discuss studies showing that mutations in APP and presenilins can contribute to AD pathology by amyloid-independent mechanisms. […] Recent evidence shows that mutations of PS1 and APP (or APP gene duplication), independently of A, directly disrupt autophagy or alter endocytosis, which impairs neuronal function and reduces neuron survival.

• #1 Amyloid-Independent Mechanisms in Alzheimer’s Disease Pathogenesis | Journal of Neuroscience

  https://www.jneurosci.org/content/30/45/14946

  Interestingly, impaired autophagy in the AD brain results in A accumulation in autolysosomes, and this reservoir of intracellular A may exert further toxicity to the lysosome system. […] It has been proposed that PS FAD mutations promote neurodegeneration by increasing neurotoxic peptide A42. More recent work, however, shows that many FAD mutants increase neither production of 42 nor the A42/40 ratio that has been thought to initiate AD pathology. […] The presenilin genes harbor most of the FAD-linked mutations and are highly expressed in pyramidal neurons of the adult cerebral cortex, where AD pathogenesis manifests. […] The fact that synaptic impairments precede progressive neurodegeneration suggests that synaptic dysfunction caused by loss of PS function promotes subsequent neuronal degeneration.

• #1 Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-01911-3

  Lysosomes rely on a rich array of acidic hydrolases to selectively degrade and recycle both intracellular and extracellular materials, playing a crucial role in maintaining cellular homeostasis. […] The BBB not only allows highly selective permeability of substances entering and exiting through specialized structures but also dynamically regulates cerebral blood flow through the process of neurovascular coupling, maintaining homeostasis and neuronal function in the CNS.

• #1 New mechanism uncovered in early stages of Alzheimer’s disease

  https://medicalxpress.com/news/2024-04-mechanism-uncovered-early-stages-alzheimer.html

  Alzheimer’s disease (AD) remains one of the most challenging and prevalent neurodegenerative disorders, affecting millions of individuals worldwide. In a new study published in Developmental Cell, researchers from the lab of Wim Annaert (VIB-KU Leuven) have identified a novel mechanism potentially connected to the early stages of AD. They demonstrated that a fragment of the amyloid precursor protein (APP), called APP-CTF, disrupts communication between cellular compartments crucial for calcium storage and waste disposal, which could be an early event preceding neuronal cell death. […] The new research, however, suggests that there might even be earlier events happening in the AD brain before plaque formation and that the APP protein plays a role in these early stages. The mechanism behind this remained a mystery until now.

• #1 Amyloid-Independent Mechanisms in Alzheimer’s Disease Pathogenesis | Journal of Neuroscience

  https://www.jneurosci.org/content/30/45/14946

  Collectively, these genetic and electrophysiological studies demonstrated that loss of presenilin function impairs LTP induction and glutamatergic neurotransmitter release by a presynaptic mechanism. […] In conclusion, we think that p25/Cdk5 concurrently exerts two parallel processes within the neuron. One aspect involves deficits in synaptic plasticity, and learning and memory in which p25/Cdk5 leads to increased -amyloid, which in turn contributes to synaptic impairments and memory loss.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20241018/New-study-reveals-molecular-mechanism-in-Alzheimers-disease.aspx

  A research team at the Institute of Neurosciences of the University of Barcelona (UBneuro) has led a study describing a new molecular mechanism that affects RNA processing and alters the process of protein synthesis in the brains of Alzheimer’s patients. […] Now, this study reveals a previously unknown role for the RTP801 protein, a stress response factor that is abundant in patients with neurodegenerative diseases such as Alzheimer’s disease. According to the findings, this protein can alter the molecular mechanisms that support neuronal survival by affecting the translation of RNA into proteins. […] The study describes how the RTP801 factor negatively regulates the activity of the tRNA ligase complex(tRNA-LC), which is critical for processing RNA molecules. In the context of Alzheimer’s disease, higher levels of RTP801 can inhibit this complex and cause problems in RNA splicing and subsequent production of relevant proteins, such as brain-derived neurotrophic factor (BDNF), exacerbating cognitive problems in a mouse model of Alzheimer’s disease.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20241018/New-study-reveals-molecular-mechanism-in-Alzheimers-disease.aspx

  Altered RNA processing a consequence of high levels of RTP801 is highly detrimental to neurons, disrupting their ability to synthesize proteins and respond to stress. […] „We now bring to the table the toxicity of unbound RNAs and its consequences as a new neurodegenerative mechanism in Alzheimer’s”, she says. […] The discovery of new functions of the RTP801 protein could open up future therapeutic options to address the treatment of neurodegenerative pathologies and preserve brain function and neuronal health.

• #1 The Amyloid-β Pathway in Alzheimer’s Disease | Molecular Psychiatry

  https://www.nature.com/articles/s41380-021-01249-0

  The glymphatic system was proposed as a CSF-ISF exchange system in absence of direct lymphatic access to the brain and with astrocytes as cellular links between brain parenchyma and the perivascular pathway. […] A species can interact with microglial and astrocytic pattern recognition receptors that initiate innate immunity where sustained microenvironment alterations such as brain accumulation of A can trigger microglia priming. […] The spatiotemporal relationship between A and glial cells, which are the critical orchestrators of neuroinflammation, is a rapidly expanding area of research to determine whether neuroinflammation can trigger and sustain incipient A dyshomeostasis, or compensate for it, or carry out both in a stage-dependent manner. […] A pathophysiology may function as a trigger/facilitator of downstream molecular pathways, including tau misfolding, tau-mediated toxicity, accumulation in tangles, and tau spreading that leads to cortical neurodegeneration. […] These findings support the hypothesis that cortical A is permissive for the spread of tangles from the medial temporal lobe associated with cognitive decline in AD.

• #1 SciELO Brasil – Insights into Alzheimer disease pathogenesis from studies in transgenic animal models Insights into Alzheimer disease pathogenesis from studies in transgenic animal models

  https://www.scielo.br/j/clin/a/t7cJSxGY36K7dHVNB3BfbJc/?lang=en

  Studies in a transgenic animal model of AD that exhibits marked neuronal and synaptic loss indicate that alterations in synaptic integrity precede neuronal loss, which is in accordance with the hypothesis that synaptic loss is one of the earliest events in AD pathogenesis. […] Furthermore, evidence from AD transgenic mouse models supports the notion that Ab may directly or indirectly interact with Tau to accelerate neurofibrillary tangle formation.

• #1 The Amyloid-β Pathway in Alzheimer’s Disease | Molecular Psychiatry

  https://www.nature.com/articles/s41380-021-01249-0

  A released at the synaptic cleft has a critical role in sustaining neuronal bioenergetic levels essential for proper synaptic activity. […] The average fractional rates of A production and clearance in cognitively healthy adults are estimated to be around 8% per hour. […] It is hypothesized that small reductions in A clearance from the brain are sufficient to cause A accumulation since efficient clearance is vital for A homeostasis and preventing its toxic accumulation in misfolded assemblies given continual APP processing and A generation. […] In physiological conditions, the BBB protects the CNS from exposure to toxic metabolites in the systemic circulation and maintains the highly regulated brain internal milieu. […] The core structure of the BBB is represented by endothelial cells connected by tight junctions, astrocytic end-feet, pericytes, and smooth muscle cells that ensure a selectively permeable system.

• #1 Alzheimer’s disease – the journey of a healthy brain into organ failure | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-022-00523-1

  Thus, it is possible that A aggregate mediated activation of glial cells and microglial in particular could trigger tau pathology, neurodegeneration and alter function of many different cells in the brain. […] The presence of AD pathologies may make the brain more vulnerable to additional insults. […] This multi-hit concept of AD pathogenesis fits well with the typical protracted time-course, the imprecise correlations between symptoms and underlying pathologies, and real-world data that shows, for example, that even small strokes in individuals with early stage AD have major impact on disease course.

• #1 Alzheimer’s disease – the journey of a healthy brain into organ failure | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-022-00523-1

  As the most common dementia, Alzheimers disease (AD) exacts an immense personal, societal, and economic toll. […] Today, we have mechanistic insight into select aspects of AD pathogenesis and have the ability to clinically detect and diagnose AD and underlying AD pathologies in living patients. These insights demonstrate that AD is a complex, insidious, degenerative proteinopathy triggered by A aggregate formation. Over time A pathology drives neurofibrillary tangle (NFT) pathology, dysfunction of virtually all cell types in the brain, and ultimately, overt neurodegeneration. […] To ensure the current lexicon surrounding AD changes from inevitable, incurable, and poorly manageable to a lexicon of preventable, curable, and manageable we must address these knowledge gaps, develop therapies that have a bigger impact on clinical symptoms or progression of disease and use these interventions at the appropriate stage of disease.

• #1 Transposable elements and Alzheimer’s disease pathogenesis. | Feil Family Brain & Mind Research Institute

  https://brainandmind.weill.cornell.edu/transposable-elements-and-alzheimers-disease-pathogenesis

  Alzheimer’s disease (AD) is characterized by the pathological accumulation of amyloid (A) plaques and neurofibrillary tangles composed of hyperphosphorylated tau. […] Microglia and astrocytes respond to the abnormal presence of tau protein with induced transposable element (TE) transcription. […] we discuss new data that link dysregulated TE expression to AD pathogenesis.

• #1 AI Helps Unravel a Cause of Alzheimer’s Disease and Identify a Therapeutic Candidate

  https://today.ucsd.edu/story/ai-helps-unravel-a-cause-of-alzheimers-disease-and-identify-a-therapeutic-candidate

  A new study found that a gene recently recognized as a biomarker for Alzheimers disease is actually a cause of it, due to its previously unknown secondary function. […] In a follow-up study, they later found that expression levels of the PHGDH gene directly correlated with changes in the brain in Alzheimers disease; in other words, the higher the levels of protein and RNA produced by the PHGDH gene, the more advanced the disease. […] Thus, the researchers established that PHGDH is indeed a causal gene to spontaneous Alzheimers disease. […] And such a disturbance can cause issues, like the development of Alzheimers disease. […] In other words, PHGDH has a previously unknown role, independent of its enzymatic function, that through a novel pathway leads to spontaneous Alzheimers disease.

• #1 AI Helps Unravel a Cause of Alzheimer’s Disease and Identify a Therapeutic Candidate

  https://today.ucsd.edu/story/ai-helps-unravel-a-cause-of-alzheimers-disease-and-identify-a-therapeutic-candidate

  That ties back to the teams earlier studies: the PHGDH gene produced more proteins in the brains of Alzheimers patients compared to the control brains, and those increased amounts of the protein in the brain triggered the imbalance. […] The critical pathway discovered in this study is upstream, so preventing this pathway can reduce amyloid plaque formation in the first place. […] With more testing, they saw that NCT-503 does indeed inhibit PHGDHs regulatory role. […] The treated mice demonstrated substantial improvement in their memory and anxiety tests. […] There may be entirely new classes of small molecules that can potentially be leveraged for development into future therapeutics.

• #1 Alzheimer’s Disease Pathogenesis – Core Concepts, Shifting Paradigms and Therapeutic Targets | IntechOpen

  https://www.intechopen.com/books/434

  Alzheimer’s Disease Pathogenesis: Core Concepts, Shifting Paradigms, and Therapeutic Targets, delivers the concepts embodied within its title. This exciting book presents the full array of theories about the causes of Alzheimer’s, including fresh concepts that have gained ground among both professionals and the lay public. Acknowledged experts provide highly informative yet critical reviews of the factors that most likely contribute to Alzheimer’s, including genetics, metabolic deficiencies, oxidative stress, and possibly environmental exposures. […] Evidence that Alzheimer’s resembles a brain form of diabetes is discussed from different perspectives, ranging from disease mechanisms to therapeutics. This book is further energized by discussions of how neurotransmitter deficits, neuro-inflammation, and oxidative stress impair neuronal plasticity and contribute to Alzheimer’s neurodegeneration. […] This book inspires confidence that effective treatments could be developed based upon the expanding list of potential therapeutic targets.

• #1 Alzheimer’s Disease: Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/9164-alzheimers-disease

  Experts are still studying Alzheimers disease to learn more about what exactly causes these proteins to build up. Researchers think the protein build-up happens a long time before it causes symptoms. It might happen up to 10 years before you notice any changes. […] Lecanemab and donanemab are intravenous (IV) infusions. Theyre two types of monoclonal antibodies. These are medications that can help your bodys immune system target and destroy amyloid proteins. They can slow down Alzheimers progression by getting rid of some of the amyloid before it damages your brain. […] Like all other treatments, these medications arent cures for Alzheimers disease. And they cant reverse any damage that amyloid has already done.

• #1 A Newly Identified Mechanism of Microglia in Alzheimer’s Disease Opens Doors to New Treatment Targets

  https://reports.mountsinai.org/article/neuro2024-03-microglia-alzheimers-disease-yue-choi

  This finding suggests that autophagy seems to guard microglia against senescence, enabling them to continue engaging with beta-amyloid plaques to keep them contained. […] This study suggests that zeroing in on microglia may be a promising treatment approach. […] If this cellular senescence phenotype is strongly associated with human Alzheimers disease, it would be meaningful to determine whether it might be useful as a biomarker. […] When the brain ages, microglia function declines. […] If we can understand the mechanism, we could potentially change the course of neurodegenerative diseaseand maybe even target microglia as an antiaging regimen.

• #1 Molecular clean-up mechanism removes plaques in Alzheimer’s disease – BioTechniques

  https://www.biotechniques.com/neuroscience/molecular-clean-up-mechanism-removes-plaques-in-alzheimers-disease/

  Researchers have produced a monoclonal antibody capable of encouraging the breakdown of plaques associated with Alzheimers disease in mice. […] The formation of amyloid plaques in the brain is a hallmark of AD. Microglia, resident immune cells in the brain and spinal cord, can wrap around these plaques to prevent their spread. Microglia also have the potential to engulf, degrade and clear amyloid plaques, but this capability is typically inhibited in AD. It is thought that this inhibition occurs due to interaction between Apolipoprotein E (ApoE) protein present in amyloid plaques and LILRB4 surface proteins present on microglia and expressed to a greater extent in individuals with AD. […] These findings suggest that disruption of the inhibitory association between LILRB4 on microglia and ApoE in amyloid plaques in individuals with AD presents a promising new avenue for AD treatment. […] By activating microglia generally, our antibody can remove amyloid beta plaques in mice, and it could potentially clear other damaging proteins in other neurodegenerative diseases, including Parkinsons disease.

• #1 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20250505/Researchers-unravel-the-genetic-contributions-to-familial-Alzheimers-disease-development.aspx

  In this study, researchers noticed direct and linear relationships between the proportion of long-to-short A fragments and the age of onset of the disease. These parallel relationships shifted across genes, which suggests the presence of a common pathogenic mechanism with gene-specific onset timings. […] „Our data predicts that a 12% shift in A profile could delay the age of onset in familial Alzheimer’s disease by up to 5 years,” says Prof. Luca Chvez Gutirrez. „This highlights the potential of therapies that target -secretase in the brain to create shorter forms of A, and in turn delay or prevent disease onset.” […] This dual-role framework enhances the ability of researchers to interpret genetic data and understand the complex interplay of factors influencing familial Alzheimer’s disease progression. Not only that, but it also supports new avenues for therapeutic interventions in familial Alzheimer’s, and potentially in more common forms of the disease.

• #1 CNS Therapeutics | Anavex Life Sciences | New York

  https://www.anavex.com/

  The activation of SIGMAR1 by ANAVEX2-73 (Blarcamesine) presents a scalable potential therapeutic solution for Alzheimer’s disease (AD) by countering neurodegeneration and improving autophagy. […] Autophagy is a key clearance mechanism that removes protein aggregates and misfolded proteins. […] Our proprietary SIGMACEPTOR platform produces orally available therapeutic candidates that lead to the modulation of SIGMAR1. Data suggests that activation of SIGMAR1 results in the restoration of upstream compensatory activities within the body, pivotal to neural cell homeostasis and neuroplasticity. […] Orally administered ANAVEX2-73 (blarcamesine) is a novel, investigational small molecule that activates an upstream compensatory process. Blarcamesine is a scalable potential therapeutic solution for Alzheimers disease by countering neurodegeneration and improving autophagy a key clearance mechanism that removes protein aggregates and misfolded proteins.

• #1 Pathogenesis of Alzheimer’s disease and therapeutic strategies involving traditional Chinese medicine – RSC Medicinal Chemistry (RSC Publishing)

  https://xlink.rsc.org/?DOI=D4MD00660G

  Pathogenesis of Alzheimer’s disease and therapeutic strategies involving traditional Chinese medicine […] Alzheimer’s disease (AD) is a prevalent degenerative disorder affecting the central nervous system of the elderly. Patients primarily manifest cognitive decline and non-cognitive neuro-psychiatric symptoms. Currently, western medications for AD primarily include cholinesterase inhibitors and glutamate receptor inhibitors, which have limited efficacy and accompanied by significant toxic side effects. Given the intricate pathogenesis of AD, the use of single-target inhibitors is limited. […] Numerous studies demonstrate that TCM and its active ingredients can exert anti-Alzheimer’s effects by modulating pathological protein production and deposition, inhibiting tau protein hyperphosphorylation, apoptosis, inflammation, and oxidative stress, while enhancing the central cholinergic system, protecting neurons and synapses, and optimizing energy metabolism. This article summarizes extracts from TCM and briefly elucidates their pharmacological mechanisms against AD, aiming to provide a foundation for further research into the specific mechanisms of TCM in the prevention and treatment of the disease, as well as the identification of efficacious active ingredients.

• #2 Alzheimer’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Alzheimer%27s_disease

  Alzheimer’s disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. The causes of Alzheimer’s disease remain poorly understood. The progression of the disease is largely characterised by the accumulation of malformed protein deposits in the cerebral cortex, called amyloid plaques and neurofibrillary tangles. These misfolded protein aggregates interfere with normal cell function, and over time lead to irreversible degeneration of neurons and loss of synaptic connections in the brain. Alzheimer’s disease is believed to occur when abnormal amounts of amyloid beta (A), accumulating extracellularly as amyloid plaques and tau proteins, or intracellularly as neurofibrillary tangles, form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function. The most predominant hypothesis is the amyloid beta (A) hypothesis. Alzheimer’s disease has been identified as a protein misfolding disease, a proteopathy, caused by the accumulation of abnormally folded amyloid beta protein into amyloid plaques, and tau protein into neurofibrillary tangles in the brain. The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau as paired helical filaments. Eventually, they form neurofibrillary tangles inside neurons. Evidence supports A as playing a central role in the pathogenesis of AD, but it does not completely explain the condition, as individuals may have normal cognition and very high A burden in their brains at an advanced age. Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer’s disease. Microglia are topographically associated with pTau and A within the brain, even when each pathologic component occurs in distinct brain regions, and microglial activation has been documented in those with mild cognitive impairment, suggesting that microglial dysfunction may precede plaque deposition as an inciting event in AD.

• #2 Mechanisms of Alzheimer’s Disease Pathogenesis and Prevention: The Brain, Neural Pathology, N-methyl-D-aspartate Receptors, Tau Protein and Other Risk Factors

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5290713/

  The characteristic features of Alzheimers disease (AD) are the appearance of extracellular amyloid-beta (A) plaques and neurofibrillary tangles in the intracellular environment, neuronal death and the loss of synapses, all of which contribute to cognitive decline in a progressive manner. […] A number of hypotheses have been proposed that may explain AD pathogenesis: (a) the A-amyloid hypothesis, (b) the A-amyloid oligomer hypothesis, (c) the presenilin hypothesis, (d) the Ca2+ dysregulation hypothesis, (e) the lysosome hypothesis, and (f) the tau hypothesis. […] A is the most widely studied component of AD pathogenesis. The amyloid hypothesis broadly posits that excessive amounts of A peptide in the brain (particularly A42) are responsible for AD-related pathology, including amyloid plaques, neurofibrillary tangles, synapse loss, and eventual neuronal cell death.

• #2 Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-01911-3

  Alzheimers disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate and diverse, stemming from a combination of factors such as aging, genetics, and environment. Our current understanding of AD pathologies involves various hypotheses, such as the cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, and abnormal autophagy. Nonetheless, unraveling the interplay among these pathological aspects and pinpointing the primary initiators of AD require further elucidation and validation. […] The etiology of AD is complex and diverse, and the precise mechanisms underlying its onset are not yet completely understood. Beyond the pivotal role of A and tau, a spectrum of other factors may contribute to the pathology of AD, such as acetylcholine deficiency, neuroinflammation, oxidative stress, biometal dyshomeostasis, glutamate imbalance, insulin resistance, gut microbiome abnormalities, cholesterol homeostasis disruption, mitochondrial dysfunction, and autophagy abnormalities.

• #2 Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies | Signal Transduction and Targeted Therapy

  https://www.nature.com/articles/s41392-024-01911-3

  The accumulation of A is a hallmark pathological feature in both extensively studied autosomal dominant AD and sporadic late-onset AD patients. A originates from the processing of the APP, a transmembrane glycoprotein, through its sequential cleavage by -secretase and -secretase (a multiprotein complex with PS1 or PS2 as catalytic subunits). […] The amyloid cascade has been proposed for over 30 years, which provided crucial insights into the mechanisms of AD’s onset and progression. […] Tau protein exhibits a spatial and temporal distribution that strongly correlates with clinical symptoms, making it a highly specific pathological biomarker in AD patients. […] Neuroinflammation is generally characterized as a chronic inflammatory response in the central nervous system (CNS) that fails to resolve on its own.

• #2 Alzheimer’s disease – the journey of a healthy brain into organ failure | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-022-00523-1

  Study of these rare genetic forms of AD have provided the framework for the ACH and our current understanding of AD at least with respect to the initial causal triggers of disease. […] They do so in three distinct ways: increasing total A production, increasing the relative production of long A peptides (typically A42 but sometimes A43) or altering the sequence of A itself in a way that promotes its aggregation. […] In contrast, the protective variant in APP found in Iceland is associated with decreased A production, and confers life-long protection from AD and cognitive decline. […] These findings serve as the fundamental observation that supports the ACH, which in its simplest form posits that A aggregation, as amyloid, is the initiating event in AD. […] However, the accumulation of A is still quite gradual typically preceding onset of symptoms by at least 20-30 years.

• #2 The role of amyloid β in the pathogenesis of Alzheimer’s disease | Journal of Clinical Pathology

  https://jcp.bmj.com/content/66/5/362

  The amyloid- peptide (A) is widely considered to be the major toxic agent in the pathogenesis of Alzheimer’s disease, a condition which afflicts approximately 36 million people worldwide. […] Despite support from numerous experimental models, important questions linger regarding the role of the A oligomer in particular. […] It is likely a huge array of oligomers, rather than a single species, which cause toxicity. […] Reappraisal of the role of the A fibril points towards a dynamic relationship with the A oligomer within an integrated system, as supported by evidence from microglia. […] However, some continue to doubt the pathological role of amyloid, instead proposing a protective role. […] If the field is to progress, all A oligomers should be characterised, the nomenclature revised and a consistent experimental protocol defined. […] Such action must surely be taken if amyloid-based therapeutic endeavour is to progress.

• #2 Insights into Alzheimer disease pathogenesis from studies in transgenic animal models | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-insights-into-alzheimer-disease-pathogenesis-S1807593222015836

  In summary, the Alzheimer disease mouse models have been the key to understanding the roles of soluble -amyloid oligomers in disease pathogenesis, as well as of the relationship between -amyloid and Tau pathologies. […] The dysfunction of APP metabolism and the consequent accumulation of A peptides and their aggregation in the form of senile plaques in the brain parenchyma of individuals with AD, have been considered crucial for neurodegeneration in the disease. This is the so-called amyloid cascade hypothesis. […] However, more recently, soluble oligomers of A peptide have been correlated with synaptic loss in the brain of AD subjects. […] The existing AD transgenic mouse models have shown considerable utility in deciphering the pathobiology of CAA. […] Analyses of the brain of APP transgenic mouse models in which large amounts of A have accumulated in plaques but no neurodegeneration has developed, such as PDAPP, Tg2576, TgCRND8, and APP23 mice, provide no or very sparse support for the well-established amyloid cascade hypothesis.

• #2 Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-020-00391-7

  APP deficiency increases KCC2 degradation via tyrosine-phosphorylation and ubiquitination, therefore, leading to GABA reversal potential depolarization and impairment during GABAA receptor-mediated inhibition. […] The amyloidogenic pathway comprises sequential proteolytic cleavage of APP by -secretase and the -secretase complex. […] Therefore, A42 is thought to be a key player in initiating plaque formation and AD pathogenesis. […] Dysregulated APP processing may contribute to AD pathogenesis by elevating A production, and reducing the A40/42 ratio. […] Tau is a microtubule-binding protein, which can undergo various types of post-translational modifications (PTMs), such as phosphorylation and truncation. […] Aberrant PTMs induces tau dissociation from microtubules, leading to tau aggregation and oligomer formation.

• #2 Alzheimer’s disease: pathogenesis, diagnostics, and therapeutics

  https://pmc.ncbi.nlm.nih.gov/articles/PMC6650620/

  GSK3 and CDK5 are the kinases primarily responsible for phosphorylation of . […] Abnormal processing of APP leads to secretion of A, which affects GSK3 kinases, leading phosphorylation of the protein. This leads to aggregation of filaments that are insoluble and finally formation of huge masses of NFTs in neurons. […] In addition to extracellular A plaques and NFTs due to hyperphosphorylation, microglial infiltration in response to these aggregates exacerbates AD pathogenesis. […] A rare mutation of TREM2 (R47H) has been reported that plays a potent role in aggravating the risk of developing AD. […] Understanding all these factors and then designing therapeutics specific to targeting them is the need of the hour.

• #2 The Amyloid-β Pathway in Alzheimer’s Disease | Molecular Psychiatry

  https://www.nature.com/articles/s41380-021-01249-0

  The glymphatic system was proposed as a CSF-ISF exchange system in absence of direct lymphatic access to the brain and with astrocytes as cellular links between brain parenchyma and the perivascular pathway. […] A species can interact with microglial and astrocytic pattern recognition receptors that initiate innate immunity where sustained microenvironment alterations such as brain accumulation of A can trigger microglia priming. […] The spatiotemporal relationship between A and glial cells, which are the critical orchestrators of neuroinflammation, is a rapidly expanding area of research to determine whether neuroinflammation can trigger and sustain incipient A dyshomeostasis, or compensate for it, or carry out both in a stage-dependent manner. […] A pathophysiology may function as a trigger/facilitator of downstream molecular pathways, including tau misfolding, tau-mediated toxicity, accumulation in tangles, and tau spreading that leads to cortical neurodegeneration. […] These findings support the hypothesis that cortical A is permissive for the spread of tangles from the medial temporal lobe associated with cognitive decline in AD.

• #2 Pathophysiology and management of alzheimer’s disease: an overview – MedCrave online

  https://medcraveonline.com/JAPLR/pathophysiology-and-management-of-alzheimerrsquos-disease-an-overview.html

  Alzheimers disease (AD) is generally considered as disorders related to intensify loss of neurons and synapses proceeds in distinct anatomical loci, resulting in different phenotypes. […] The pathophysiology of Alzheimer’s disease is credited to a number of factors such as the cholinergic dysfunction, amyloid/tau toxicity and oxidative stress/mitochondrial dysfunction. […] The accretion of tau proteins correlates very closely with cognitive decline and brain atrophy, including hippocampal atrophy. […] In the neuropathology of Alzheimers disease there is a loss of neurons and atrophy in temporofrontal cortex, which causes inflammation and deposit the amyloid plaques and an abnormal cluster of protein fragments and tangled bundles of fibers due to this there is an increase in the presence of monocytes and macrophages in cerebral cortex and it also activates the microglial cells in the parenchyma.

• #2 Pathophysiology and management of alzheimer’s disease: an overview – MedCrave online

  https://medcraveonline.com/JAPLR/pathophysiology-and-management-of-alzheimerrsquos-disease-an-overview.html

  The pathophysiology of Alzheimer’s disease is credited to a number of factors such as the cholinergic dysfunction, amyloid/tau toxicity and oxidative stress/mitochondrial dysfunctions. […] The effects of apo-lipo-protein E (APOE) genotype on the useful effect of acetyl-cholinesterase inhibitors (AChEIs) in patients with Alzheimers disease. […] The amyloid cascade theory postulates that the neurodegeneration in AD caused by the abnormal accretion of amyloid beta (A) plaques in many areas of the brain. […] The study of disease-initiating mechanisms and AD progression in humans is inherently difficult as most available tissue specimens are from late-stages of the disease. […] Amyloid hypothesis places the A peptide as the principal factor that triggers the pathological cascade that leads to the dementia and other symptoms of AD.

• #2 An Insight into Cellular and Molecular Mechanisms Underlying the Pathogenesis of Neurodegeneration in Alzheimer’s Disease

  https://www.mdpi.com/2227-9059/11/5/1398

  An Insight into Cellular and Molecular Mechanisms Underlying the Pathogenesis of Neurodegeneration in Alzheimer’s Disease […] Alzheimer’s disease (AD) is the most prominent neurodegenerative disorder in the aging population. It is characterized by cognitive decline, gradual neurodegeneration, and the development of amyloid-β (Aβ)-plaques and neurofibrillary tangles, which constitute hyperphosphorylated tau. […] Emerging evidence over the past few decades supports the critical role of Aβ and tau in AD pathogenesis and the participation of glial cells in different molecular and cellular pathways. This review extensively discusses the current understanding concerning Aβ- and tau-associated molecular mechanisms and glial dysfunction in AD. […] The neurodegenerative disorder called Alzheimer’s disease mainly proceeds from brain cell degeneration, and ultimately leads to demise following dementia. […] Two distinct types of aggregates are the primary neuropathological indicators of AD. The first is an extracellular amyloid (Aβ) peptide deposit (plaques). The second is hyperphosphorylated Tau protein fibrillary aggregation (tangles). It is typically proposed that neuroinflammation is another pathogenic characteristic of AD. […] Normal aging allows the brain to shrink somewhat, yet oddly enough, a considerable proportion of neurons are not lost. Unfortunately, in the case of AD, many neurons stop functioning, break connectivity with the surrounding neurons, and ultimately die, causing significant harm. […] The symptoms of AD change with the phases of the disease. AD is categorized into three stages: preclinical or pre-symptomatic, mild, and dementia-stage, depending on the extent of cognitive deterioration. […] For over three decades, the amyloid hypothesis has been the dominant and most widely accepted mechanistic theory of how AD develops. According to their theory, the accumulation of oligomeric Aβ (oAβ)-peptides are responsible for the pathophysiology causing downstream events such as neuroinflammation, the formation of neurofibrillary tangles (NFT), and vascular injury, encouraging dementia and cognitive deficits. […] The primary element that significantly contributes to the pathophysiology of AD and is often regarded as the principal reason for AD development is the amyloid β peptide. […] Tau is a cytosol protein mostly available in axons and is a neuronal microtubule-associated protein. […] The presence of Aβ, neural inflammation, enzymes, and oxidative stress that modulate phosphatases and kinases can all impact the phosphorylated tau-protein conformation. […] The formation of Tau into neurofibrillary tangles is in close alliance with the neurodegeneration (i.e., neural demise) and brain atrophy seen in AD. […] According to multiple evidence-based studies, the pathophysiology of AD may be influenced by mitochondrial dysfunction. […] The idea that oxidative stress might be what causes AD pathogenesis triggered by Aβ is supported by the finding that oxidative stress emerges earlier in AD. […] Nitrosative stress arises when various defensive mechanisms fail to balance the formation of reactive nitrogen species (RNS), which harms intracellular constituents. […] Multiple evidence-based findings imply that ROS might be crucial in the emergence of neurodegeneration in AD. […] DNA is nucleic acid found in the mitochondria (mtDNA) and nuclear (nDNA) material of living cells. […] Another characteristic of AD is neuroinflammation, which appears as gliosis and is marked by the activation and proliferation of the two main glial cell types in the brain, astrocytes and microglia. […] In AD, inappropriate Aβ collection seems to be what starts the inflammatory processes. […] Considering that several tau transgenic animal models and tauopathy sufferers exhibit gliosis even in the absence of Aβ pathology, pathogenic tau species can also activate microglia and astrocytes. […] By eliminating proteins that are inappropriately folded or clumped together, the ubiquitin-proteasome pathway (UPP) helps to maintain cellular integrity. […] In the case of neuroinflammation, serum and brain specimens from AD patients include inflammatory mediators such TNF-α, IL-6, IL-β, and cyclooxygenase-2 (COX-2).

• #2 Mathematical Modeling for the Pathogenesis of Alzheimer’s Disease | PLOS One

  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015176

  Although the deposition of amyloid- (A) peptides and formation of senile plaques in the brain is the cardinal morphological feature identifying the clinical phenotype of AD, increasing clinical and basic studies suggest that inflammatory activation of microglia may play an equally important role during the initiation and progression of the disease. […] The multiple positive and negative feedbacks among these cells are thus crucial for neurodegeneration that eventually alters the neuronal structure and function during the pathogenesis of AD. […] Here, we evaluate the dynamic network involving multiple cross-talks among distinct states of microglia, astroglia, and neurons through a mathematical model. Our approach has led to an intriguing insight suggesting that microglia activation in addition to a threshold for A may be the critical initiator for the pathogenesis of AD.

• #2 A Newly Identified Mechanism of Microglia in Alzheimer’s Disease Opens Doors to New Treatment Targets

  https://reports.mountsinai.org/article/neuro2024-03-microglia-alzheimers-disease-yue-choi

  This finding suggests that autophagy seems to guard microglia against senescence, enabling them to continue engaging with beta-amyloid plaques to keep them contained. […] This study suggests that zeroing in on microglia may be a promising treatment approach. […] If this cellular senescence phenotype is strongly associated with human Alzheimers disease, it would be meaningful to determine whether it might be useful as a biomarker. […] When the brain ages, microglia function declines. […] If we can understand the mechanism, we could potentially change the course of neurodegenerative diseaseand maybe even target microglia as an antiaging regimen.

• #2 Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-020-00391-7

  Tau aggregates can induce mitochondria fragmentation, impair synaptic vesicle mobility and release, thereby leading to presynaptic dysfunction. […] In addition, pathological tau species can activate microglial NF-B and NLRP3 inflammasome pathways, leading to pro-inflammatory cytokine release. […] Together, these results suggest that synaptogyrin-3 is a key modulator for tau-induced presynaptic dysfunction.

• #2 Mechanisms of Alzheimer’s Disease Pathogenesis and Prevention: The Brain, Neural Pathology, N-methyl-D-aspartate Receptors, Tau Protein and Other Risk Factors

  https://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2017.15.1.1

  Imaging of amyloid plaques reveals the rapid formation of plaque structures over a 24 hour time period; dystrophic swelling of adjacent dendrites begins to appear within one week. […] The pathogenesis of AD is strongly associated with alterations in glutamate signaling and the tissues affected by AD contain high densities of glumatergic neurons. […] Excitotoxicity occurs as a result of the chronic, moderate activation of NMDA receptors, leading to neurodege-neration. […] The excitotoxicity hypothesis is supported by clinical evidence indicating that the NMDA receptor antagonist memantine slows AD progression. […] Tau phosphorylation was also proposed as a potential contributor to the formation of neurofibrillary tangles in AD. […] Hyperphosphorylated tau thus has an important role in intracellular neurofibrillary changes and the pathogenesis of AD and related tauopathies. […] Cumulatively, preclinical observations have suggested that deficient BDNF synthesis contributes to neuronal dysfunction in AD.

• #2 The Complex Pathogenesis and Genetics of Alzheimer’s Disease | MedPage Today

  https://www.medpagetoday.com/medical-journeys/alzheimers-disease/111933

  Once amyloid pathology is underway, it predicts intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles and that, in turn, predicts onset of cognitive impairment. […] Hyperphosphorylated tau can impair synaptic function. […] Activation of immune mediators appears to be a critical regulator of Alzheimer’s disease pathology, including reactive astrogliosis and microgliosis. […] An underlying infectious basis for the disease has long been speculated, with certain pathogens infecting the brain and kick-starting Aβ fibrillization as an antimicrobial defense mechanism which then seeds further deposition. […] Sleep impairment and deprivation have also been shown to stimulate higher Aβ and tau levels in human cerebrospinal fluid and animal model brains. […] ApoE protein is a lipid-binding protein expressed at the highest levels in the liver and brain, where it binds directly to Aβ present in plaques.

• #2 ALZHEIMER’S DISEASE – Pathogenesis – Pathology Made Simple

  https://ilovepathology.com/alzheimers-disease-pathogenesis/

  Amyloid plaques are extracellular deposits of amyloid beta proteins, and neurofibrillary tangles are accumulations of hyperphosphorylated tau proteins within neurons that eventually become extracellular as the cells die. […] APOE, particularly the 4 allele, is associated with an increased risk of Alzheimers. It promotes amyloid beta generation and deposition, as well as tau-mediated neurodegeneration, even in the absence of amyloid proteins.

• #2 Amyloid-Independent Mechanisms in Alzheimer’s Disease Pathogenesis | Journal of Neuroscience

  https://www.jneurosci.org/content/30/45/14946

  Despite the genetic and cell biological evidence that supports the amyloid hypothesis, it is becoming clear that AD etiology is complex and that A alone is unable to account for all aspects of AD (Pimplikar, 2009). […] The fact that vast overproduction of A peptides in the mouse brain failed to cause neurodegeneration raises further questions as to whether accumulation of A peptides is indeed the culprit for neurodegeneration in AD. […] This article highlights the findings that were presented in a symposium and is not meant to be a comprehensive review of AD pathogenesis. Here we discuss studies showing that mutations in APP and presenilins can contribute to AD pathology by amyloid-independent mechanisms. […] Recent evidence shows that mutations of PS1 and APP (or APP gene duplication), independently of A, directly disrupt autophagy or alter endocytosis, which impairs neuronal function and reduces neuron survival.

• #2 New mechanism uncovered in early stages of Alzheimer’s disease

  https://medicalxpress.com/news/2024-04-mechanism-uncovered-early-stages-alzheimer.html

  The new study further supports that the APP-CTFs resulting from suppressing gamma-secretase might actually be the culprit behind endolysosomal dysfunction, as observed in the very early stages of AD. […] This research significantly advances our comprehension of the potential causes of disease in the early stages of AD. A remarkable outcome of this study is that these early stages could be caused by another fragment of the same APP molecule rather than Aβ. […] „The failure of clinical trials using gamma-secretase inhibitors may be explained by the fact that we were focusing on only one culprit and at a too late stage in the disease,” explains Prof. Annaert, senior author of the study. […] „Our research findings suggest that gamma-secretase modulators, which can help promote clearance of toxic APP-CTFs without blocking the enzyme completely, may be a more relevant target for early intervention in AD. The key might be finding the right balance between APP-CTF clearance and plaque prevention.”

• #2 Alzheimer’s disease – the journey of a healthy brain into organ failure | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-022-00523-1

  As the most common dementia, Alzheimers disease (AD) exacts an immense personal, societal, and economic toll. […] Today, we have mechanistic insight into select aspects of AD pathogenesis and have the ability to clinically detect and diagnose AD and underlying AD pathologies in living patients. These insights demonstrate that AD is a complex, insidious, degenerative proteinopathy triggered by A aggregate formation. Over time A pathology drives neurofibrillary tangle (NFT) pathology, dysfunction of virtually all cell types in the brain, and ultimately, overt neurodegeneration. […] To ensure the current lexicon surrounding AD changes from inevitable, incurable, and poorly manageable to a lexicon of preventable, curable, and manageable we must address these knowledge gaps, develop therapies that have a bigger impact on clinical symptoms or progression of disease and use these interventions at the appropriate stage of disease.

• #2 Pathogenesis of Alzheimer’s Disease | SpringerLink

  https://link.springer.com/10.1007/978-3-030-71519-9_162-1

  Alzheimers disease (AD) is a clinically progressive decline in cortical function involving memory and other cognitive domain of executive function and pathologically by two hallmark lesions, amyloid- plaque cores (APC) and neurofibrillary tangles (NFT). […] The ruling theories for AD pathogenesis have their root in pathological lesion removal. It is argued that pathological changes instead reflect elaborate neuroprotection mechanisms in response to a decade-long adaptation to an aging-hostile environment. […] The lesions themselves may similarly be a manifestation of neuroprotection, and likewise the targeting of such lesions as the offending agents is done at the risk of disrupting homeostasis and the bodys attempt at fighting disease. […] A broadening of the scope of treatment efforts to working with rather than against the biological responses of the brain, and the realities of repeated negative data, should now be embraced with enthusiasm.

• #2 Transposable elements and Alzheimer’s disease pathogenesis.

  https://vivo.weill.cornell.edu/display/pubid36588011

  Alzheimer’s disease (AD) is characterized by the pathological accumulation of amyloid (A) plaques and neurofibrillary tangles composed of hyperphosphorylated tau. […] In this Forum, we discuss new data that link dysregulated TE expression to AD pathogenesis.

• #2 Pathophysiology of dementia

  https://www1.racgp.org.au/ajgp/2023/august/pathophysiology-of-dementia

  CVD and AD share many vascular risk factors and often coexist in older people with dementia. […] Neuroinflammation with microglial activation has been increasingly recognised to play an important role in the pathogenesis of AD and is involved in A deposition, neuronal damage and cell death. […] Cholinergic transmission, implicated in modulating cognitive processes such as learning, memory and arousal, also plays an integral part in AD.

• #3 Alzheimer’s Disease: Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/9164-alzheimers-disease

  Alzheimers disease (AD) is the most common cause of dementia. Alzheimers is pronounced alz-HAI-mers. Its a neurodegenerative disease that affects your brain. This means it damages and destroys cells in your brain over time. Eventually, people with AD lose some of their brain functions, including memory and language. […] An abnormal build-up of proteins in your brain causes Alzheimers disease. Specifically, two proteins called amyloid and tau. […] Amyloid protein sticks together in your brain cells, forming clumps called plaques. Tau proteins twist together in fiber-like strands called tangles. The plaques and tangles prevent neurons from working as they should. They block neurons ability to send electrical and chemical signals back and forth. […] When amyloid and tau proteins build up in your brain, they slowly kill neurons. This causes permanent damage that leads to Alzheimers symptoms. Nerve cell death starts in one area of your brain and then spreads to other areas. Its most common for Alzheimers to begin in the area of your brain that controls memory your hippocampus.

• #3 Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-020-00391-7

  Alzheimers disease (AD) is the most common neurodegenerative disorder seen in age-dependent dementia. […] Studies within the last few decades provide growing evidence for a central role of amyloid (A) and tau, as well as glial contributions to various molecular and cellular pathways in AD pathogenesis. […] We also discuss other critical factors that may affect AD pathogenesis, including genetics, aging, variables related to environment, lifestyle habits, and describe the potential role of apolipoprotein E (APOE), viral and bacterial infection, sleep, and microbiota. […] Primary pathological hallmarks of AD include A plaques, neurofibrillary tangles (NFTs), gliosis, and neuronal loss, accompanied by cerebrovascular amyloidosis, inflammation and major synaptic changes. […] The extracellular domain of APP mediates cell-to-cell adhesion to support synaptic connections.

• #3 Mechanisms of Alzheimer’s Disease Pathogenesis and Prevention: The Brain, Neural Pathology, N-methyl-D-aspartate Receptors, Tau Protein and Other Risk Factors

  https://www.cpn.or.kr/journal/view.html?doi=10.9758/cpn.2017.15.1.1

  The characteristic features of Alzheimers disease (AD) are the appearance of extracellular amyloid-beta (A) plaques and neurofibrillary tangles in the intracellular environment, neuronal death and the loss of synapses, all of which contribute to cognitive decline in a progressive manner. […] A number of hypotheses have been proposed that may explain AD pathogenesis: (a) the A-amyloid hypothesis, (b) the A-amyloid oligomer hypothesis, (c) the presenilin hypothesis, (d) the Ca2+ dysregulation hypothesis, (e) the lysosome hypothesis, and (f) the tau hypothesis. […] A is the most widely studied component of AD pathogenesis. […] The amyloid hypothesis broadly posits that excessive amounts of A peptide in the brain (particularly A42) are responsible for AD-related pathology, including amyloid plaques, neurofibrillary tangles, synapse loss, and eventual neuronal cell death.

• #3 The Amyloid-β Pathway in Alzheimer’s Disease | Molecular Psychiatry

  https://www.nature.com/articles/s41380-021-01249-0

  Breakthroughs in molecular medicine have positioned the amyloid- (A) pathway at the center of Alzheimers disease (AD) pathophysiology. […] The established biochemical alterations of the A cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. […] We discuss the evidence highlighting a differentiated interaction of distinct A species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. […] This pathophysiological model has supported a considerable effort to develop therapeutic compounds targeting the A pathway to slow AD progression in early clinical stages. […] While research and physician communities have raised theoretical and conceptual questions on the scientific appeal of A-targeting therapeutic development due to the failures of AD drug clinical trials, anti-A compounds are continually investigated with promising progress of several late-stage development agents towards regulatory approval steps.

• #3 The Amyloid-β Pathway in Alzheimer’s Disease | Molecular Psychiatry

  https://www.nature.com/articles/s41380-021-01249-0

  In addition, brain A accumulation appears to be upstream to other pathomechanistic alterations of the biological continuum of AD, including the spreading of NTFs, and involvement of neuronal and synaptic loss. […] The temporal and spatial evolution of these pathophysiological alterations underlies AD cognitive and functional decline across a clinical continuum, from preclinical to prodromal and dementia stages. […] The potential pathogenic role of the APP gene in humans is supported by the existence of a rare protective variant APP A673T (or A2T) next to the APP -secretase site that reduces both APP cleavage and the production of amyloidogenic A peptides. […] The A is a 4kDa fragment of the amyloid precursor protein (APP), a larger precursor molecule widely produced by brain neurons, vascular and blood cells (including platelets), and, to a lesser extent, astrocytes.

• #3 Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease | Molecular Neurodegeneration | Full Text

  https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-020-00391-7

  APP deficiency increases KCC2 degradation via tyrosine-phosphorylation and ubiquitination, therefore, leading to GABA reversal potential depolarization and impairment during GABAA receptor-mediated inhibition. […] The amyloidogenic pathway comprises sequential proteolytic cleavage of APP by -secretase and the -secretase complex. […] Therefore, A42 is thought to be a key player in initiating plaque formation and AD pathogenesis. […] Dysregulated APP processing may contribute to AD pathogenesis by elevating A production, and reducing the A40/42 ratio. […] Tau is a microtubule-binding protein, which can undergo various types of post-translational modifications (PTMs), such as phosphorylation and truncation. […] Aberrant PTMs induces tau dissociation from microtubules, leading to tau aggregation and oligomer formation.

• #3 SciELO Brasil – Insights into Alzheimer disease pathogenesis from studies in transgenic animal models Insights into Alzheimer disease pathogenesis from studies in transgenic animal models

  https://www.scielo.br/j/clin/a/t7cJSxGY36K7dHVNB3BfbJc/?lang=en

  However, more recently, soluble oligomers of Abpeptide have been correlated with synaptic loss in the brain of AD subjects. […] Although none of the AD transgenic models fully replicates the human disease, they have suggested new insights into the pathophysiology of Ab toxicity, particularly with respect to the effects of different Ab species and the possible pathogenic role of Ab oligomers. […] Studies in APP23 mice, which developed a similar degree of both Abplaques and CAA, provided the first evidence that a neuronal source of APP/Ab is sufficient to induce cerebrovascular Ab and associated neurodegeneration. […] The existing AD transgenic mouse models have shown considerable utility in deciphering the pathobiology of CAA. […] There is accumulating evidence from AD transgenic mice that intraneuronal A1-42 triggers early neuronal loss as well as synaptic deficits.

• #3 Insights into Alzheimer disease pathogenesis from studies in transgenic animal models | Clinics

  https://www.elsevier.es/en-revista-clinics-22-articulo-insights-into-alzheimer-disease-pathogenesis-S1807593222015836

  There is now a great interest in identifying which A species (A1-40, A1-42, or truncated A) and form (oligomers or deposits) would be responsible for neurotoxicity, and in understanding the relationship between A and Tau pathologies. […] These studies indicate that intraneuronal soluble A is a pathological feature of AD that has long been neglected and is turning out to be the key factor leading to neuronal loss in the disease before the extracellular A deposition. […] Loss of neuronal synaptic density and synapse number represents another invariant feature of AD that appears to precede overt neuronal degeneration. […] There is accumulating evidence from AD transgenic mice that intraneuronal A1-42 triggers not only early neuronal loss but also synaptic deficits. […] Studies in a transgenic animal model of AD that exhibits marked neuronal and synaptic loss indicate that alterations in synaptic integrity precede neuronal loss, which is in accordance with the hypothesis that synaptic loss is one of the earliest events in AD pathogenesis. […] Finally, the AD transgenic models may allow to define and evaluate potential drug targets and to develop therapeutic strategies that might interfere or delay the onset of AD.

• #3 An Insight into Cellular and Molecular Mechanisms Underlying the Pathogenesis of Neurodegeneration in Alzheimer’s Disease

  https://www.mdpi.com/2227-9059/11/5/1398

  An Insight into Cellular and Molecular Mechanisms Underlying the Pathogenesis of Neurodegeneration in Alzheimer’s Disease […] Alzheimer’s disease (AD) is the most prominent neurodegenerative disorder in the aging population. It is characterized by cognitive decline, gradual neurodegeneration, and the development of amyloid-β (Aβ)-plaques and neurofibrillary tangles, which constitute hyperphosphorylated tau. […] Emerging evidence over the past few decades supports the critical role of Aβ and tau in AD pathogenesis and the participation of glial cells in different molecular and cellular pathways. This review extensively discusses the current understanding concerning Aβ- and tau-associated molecular mechanisms and glial dysfunction in AD. […] The neurodegenerative disorder called Alzheimer’s disease mainly proceeds from brain cell degeneration, and ultimately leads to demise following dementia. […] Two distinct types of aggregates are the primary neuropathological indicators of AD. The first is an extracellular amyloid (Aβ) peptide deposit (plaques). The second is hyperphosphorylated Tau protein fibrillary aggregation (tangles). It is typically proposed that neuroinflammation is another pathogenic characteristic of AD. […] Normal aging allows the brain to shrink somewhat, yet oddly enough, a considerable proportion of neurons are not lost. Unfortunately, in the case of AD, many neurons stop functioning, break connectivity with the surrounding neurons, and ultimately die, causing significant harm. […] The symptoms of AD change with the phases of the disease. AD is categorized into three stages: preclinical or pre-symptomatic, mild, and dementia-stage, depending on the extent of cognitive deterioration. […] For over three decades, the amyloid hypothesis has been the dominant and most widely accepted mechanistic theory of how AD develops. According to their theory, the accumulation of oligomeric Aβ (oAβ)-peptides are responsible for the pathophysiology causing downstream events such as neuroinflammation, the formation of neurofibrillary tangles (NFT), and vascular injury, encouraging dementia and cognitive deficits. […] The primary element that significantly contributes to the pathophysiology of AD and is often regarded as the principal reason for AD development is the amyloid β peptide. […] Tau is a cytosol protein mostly available in axons and is a neuronal microtubule-associated protein. […] The presence of Aβ, neural inflammation, enzymes, and oxidative stress that modulate phosphatases and kinases can all impact the phosphorylated tau-protein conformation. […] The formation of Tau into neurofibrillary tangles is in close alliance with the neurodegeneration (i.e., neural demise) and brain atrophy seen in AD. […] According to multiple evidence-based studies, the pathophysiology of AD may be influenced by mitochondrial dysfunction. […] The idea that oxidative stress might be what causes AD pathogenesis triggered by Aβ is supported by the finding that oxidative stress emerges earlier in AD. […] Nitrosative stress arises when various defensive mechanisms fail to balance the formation of reactive nitrogen species (RNS), which harms intracellular constituents. […] Multiple evidence-based findings imply that ROS might be crucial in the emergence of neurodegeneration in AD. […] DNA is nucleic acid found in the mitochondria (mtDNA) and nuclear (nDNA) material of living cells. […] Another characteristic of AD is neuroinflammation, which appears as gliosis and is marked by the activation and proliferation of the two main glial cell types in the brain, astrocytes and microglia. […] In AD, inappropriate Aβ collection seems to be what starts the inflammatory processes. […] Considering that several tau transgenic animal models and tauopathy sufferers exhibit gliosis even in the absence of Aβ pathology, pathogenic tau species can also activate microglia and astrocytes. […] By eliminating proteins that are inappropriately folded or clumped together, the ubiquitin-proteasome pathway (UPP) helps to maintain cellular integrity. […] In the case of neuroinflammation, serum and brain specimens from AD patients include inflammatory mediators such TNF-α, IL-6, IL-β, and cyclooxygenase-2 (COX-2).

• #3 Pathophysiology of dementia

  https://www1.racgp.org.au/ajgp/2023/august/pathophysiology-of-dementia

  Neurofibrillary tangles formed by phosphorylated (p-) tau proteins are one of the cardinal features of AD. Tau hyperphosphorylation causing microtubule destabilisation is generally thought to be the main pathological process driving downstream neurodegenerative damage resulting in microglial activation, synaptic loss and neuronal death. […] In AD, according to the Braak system, tau pathology typically originates in the temporal cortices and tau, rather than A, has been shown to be the main determinant of brain atrophy, cognitive changes and clinical decline in patients. […] The amyloid cascade hypothesis has remained the main pathological model in AD for decades; however, there is increasing evidence that supports multicausality of the pathophysiology of AD. […] In addition to A and tau, coexisting neuropathologies are commonly detected in individuals with AD.

• #3 Pathophysiology and management of alzheimer’s disease: an overview – MedCrave online

  https://medcraveonline.com/JAPLR/pathophysiology-and-management-of-alzheimerrsquos-disease-an-overview.html

  The pathophysiology of Alzheimer’s disease is credited to a number of factors such as the cholinergic dysfunction, amyloid/tau toxicity and oxidative stress/mitochondrial dysfunctions. […] The effects of apo-lipo-protein E (APOE) genotype on the useful effect of acetyl-cholinesterase inhibitors (AChEIs) in patients with Alzheimers disease. […] The amyloid cascade theory postulates that the neurodegeneration in AD caused by the abnormal accretion of amyloid beta (A) plaques in many areas of the brain. […] The study of disease-initiating mechanisms and AD progression in humans is inherently difficult as most available tissue specimens are from late-stages of the disease. […] Amyloid hypothesis places the A peptide as the principal factor that triggers the pathological cascade that leads to the dementia and other symptoms of AD.

• #3 Alzheimer’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Alzheimer%27s_disease

  Alzheimer’s disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. The causes of Alzheimer’s disease remain poorly understood. The progression of the disease is largely characterised by the accumulation of malformed protein deposits in the cerebral cortex, called amyloid plaques and neurofibrillary tangles. These misfolded protein aggregates interfere with normal cell function, and over time lead to irreversible degeneration of neurons and loss of synaptic connections in the brain. Alzheimer’s disease is believed to occur when abnormal amounts of amyloid beta (A), accumulating extracellularly as amyloid plaques and tau proteins, or intracellularly as neurofibrillary tangles, form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function. The most predominant hypothesis is the amyloid beta (A) hypothesis. Alzheimer’s disease has been identified as a protein misfolding disease, a proteopathy, caused by the accumulation of abnormally folded amyloid beta protein into amyloid plaques, and tau protein into neurofibrillary tangles in the brain. The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau as paired helical filaments. Eventually, they form neurofibrillary tangles inside neurons. Evidence supports A as playing a central role in the pathogenesis of AD, but it does not completely explain the condition, as individuals may have normal cognition and very high A burden in their brains at an advanced age. Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer’s disease. Microglia are topographically associated with pTau and A within the brain, even when each pathologic component occurs in distinct brain regions, and microglial activation has been documented in those with mild cognitive impairment, suggesting that microglial dysfunction may precede plaque deposition as an inciting event in AD.

• #3 The Complex Pathogenesis and Genetics of Alzheimer’s Disease | MedPage Today

  https://www.medpagetoday.com/medical-journeys/alzheimers-disease/111933

  Once amyloid pathology is underway, it predicts intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles and that, in turn, predicts onset of cognitive impairment. […] Hyperphosphorylated tau can impair synaptic function. […] Activation of immune mediators appears to be a critical regulator of Alzheimer’s disease pathology, including reactive astrogliosis and microgliosis. […] An underlying infectious basis for the disease has long been speculated, with certain pathogens infecting the brain and kick-starting Aβ fibrillization as an antimicrobial defense mechanism which then seeds further deposition. […] Sleep impairment and deprivation have also been shown to stimulate higher Aβ and tau levels in human cerebrospinal fluid and animal model brains. […] ApoE protein is a lipid-binding protein expressed at the highest levels in the liver and brain, where it binds directly to Aβ present in plaques.

• #3 The Complex Pathogenesis and Genetics of Alzheimer’s Disease | MedPage Today

  https://www.medpagetoday.com/medical-journeys/alzheimers-disease/111933

  After a long debate, a working group convened by the Alzheimer’s Disease Sequencing Project came to consensus that the APOE4 gene is definitively toxic. […] A single inherited copy of the APOE4 allele increases Alzheimer’s risk approximately three- to four-fold, while two inherited copies increase risk by some 12-fold. […] The genetic alterations of Down syndrome also mean elevated risk for Alzheimer’s disease. […] Autosomal dominant Alzheimer’s disease accounts for only a small percentage of cases (5-10%) but results in disease for nearly all who inherit mutations in one of three genes: […] All three are strongly associated with early-onset forms of the disease, with clinical symptoms appearing before age 65.

• #4 Alzheimer’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Alzheimer%27s_disease

  Alzheimer’s disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. The causes of Alzheimer’s disease remain poorly understood. The progression of the disease is largely characterised by the accumulation of malformed protein deposits in the cerebral cortex, called amyloid plaques and neurofibrillary tangles. These misfolded protein aggregates interfere with normal cell function, and over time lead to irreversible degeneration of neurons and loss of synaptic connections in the brain. Alzheimer’s disease is believed to occur when abnormal amounts of amyloid beta (A), accumulating extracellularly as amyloid plaques and tau proteins, or intracellularly as neurofibrillary tangles, form in the brain, affecting neuronal functioning and connectivity, resulting in a progressive loss of brain function. The most predominant hypothesis is the amyloid beta (A) hypothesis. Alzheimer’s disease has been identified as a protein misfolding disease, a proteopathy, caused by the accumulation of abnormally folded amyloid beta protein into amyloid plaques, and tau protein into neurofibrillary tangles in the brain. The tau hypothesis proposes that tau protein abnormalities initiate the disease cascade. In this model, hyperphosphorylated tau begins to pair with other threads of tau as paired helical filaments. Eventually, they form neurofibrillary tangles inside neurons. Evidence supports A as playing a central role in the pathogenesis of AD, but it does not completely explain the condition, as individuals may have normal cognition and very high A burden in their brains at an advanced age. Various inflammatory processes and cytokines may also have a role in the pathology of Alzheimer’s disease. Microglia are topographically associated with pTau and A within the brain, even when each pathologic component occurs in distinct brain regions, and microglial activation has been documented in those with mild cognitive impairment, suggesting that microglial dysfunction may precede plaque deposition as an inciting event in AD.

• #4 Biochemistry of Alzheimer’s disease – Wikipedia

  https://en.wikipedia.org/wiki/Biochemistry_of_Alzheimer%27s_disease

  The biochemistry of Alzheimer’s disease, the most common cause of dementia, is not yet very well understood. Alzheimer’s disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (A) protein in the brain. […] AD is also considered a tauopathy due to abnormal aggregation of the tau protein, a microtubule-associated protein expressed in neurons that normally acts to stabilize microtubules in the cell cytoskeleton. […] Neuroinflammation is also involved in the complex cascade leading to AD pathology and symptoms. […] Current theories establish that both misfolding tau protein inside the cell and aggregation of amyloid beta outside the cell initiates the cascade leading to AD pathology. […] The amyloid beta hypothesis of molecular initiation have become dominant among many researchers to date.

• #4 The Amyloid-β Pathway in Alzheimer’s Disease | Molecular Psychiatry

  https://www.nature.com/articles/s41380-021-01249-0

  The locus of the APP gene is on chromosome 21. […] Most pathogenic mutations on the APP gene cluster around the proteolytic sites of the – and -secretases with a downstream increase of the substrate affinity and either an overall increase of the total A pool or shifts in A peptides ratios. […] The opposite effects of APP A673V and APP A673T variants on amyloidogenesis indicate a distinct autosomal recessive pattern of inheritance. […] The A is identified by cerebrospinal fluid A42 assay or PET amyloid imaging. […] A is an ancient neuropeptide, highly conserved across vertebrate taxa over at least 400 million years. […] A monomers can trigger or sustain intracellular signaling essential for neurotransmission, including the regulation of the excitation/inhibition balance, and synaptic vesicle trafficking.

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