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molecular pathology of Alzheimer's disease

Pathology: 1) increased formation & deposition of amyloid a) formation & acummulation of intracellular A4/42 is the earliest event in AD [21] b) may be a feature in common with traumatic brain injury c) diminished expression of retromer complex may play role in accumulation of A4/42 [12] d) apolipoprotein E binds to the A4/42 amyloid peptide e) enhanced deposition of amyloid A4/42 peptide with apo E4 genotype [8] f) A4/42 accumulates in neurons & astrocytes - astrocytic A4/42 of neuronal origin g) prion protein PrPc (CD230) may bind & internalize A4 oligomers [13] h) in a study of a mouse model for AD, it is proposed that Abeta may exert on the CRF receptor resulting in damage to the hippocampus resulting from increased corticosteroid release in response to minor stress [22] i) higher CSF A-beta42 increases likelihood of higher neurofibrillary tangles outside of the mesial temporal lobes [23] j) lower CSF A-beta42 increases likelihood of AD [40] - A-beta42 more avidly taken up from CSF in patients with AD [40] - type of brain cells taking up A-beta42 not specified 2) hyperphosphorylation of microtubule-associated protein tau a) disulfide linkage of hyperphosphorylated tau may be linked to oxidative stress b) formation of paired helical filaments (PHF) from PHF-tau c) see microtubule-associated protein tau for protein kinases that phosphorylate tau d) formation of intracellar A4/42 is upstream of formation of PHF-tau [21] e) newly synthesized tau is truncated & actively released into CSF during neuronal activity associated with presynaptic glutamine release - rate of truncated forms of tau released into CSF positively correlates with amyloid plaque burden [26] f) isomerization of aspartic acid in a peptide from tau [36] - increase in isomer found in both autosomal dominant & sporadic AD - increase consistent with reduced autophagic flux in AD g) tau oligomer-containing synapses are engulfed by microglia & astrocytes in Braak stage 3-4 Alzheimer's dementia in the absence of neurofibrillary tangle deposition [43] 3) CSF soluble TREM2 & TREM2 expressed on microglia may play a role in facilitation of PHF-tau propagation by activated microglia in association with beta-amyloid [34] - microglial activation & PHF-tau propagate jointly across Braak stages - expression of TREM2 rises in parallel with expression of beta-amyloid in the cerebral cortex 4) PERK kinase (EIF2AK3) & the unfolded protein response may be associated with tau pathology 5) activation of inflammatory mediators a) activation of the complement system 1] interaction of A4-beta peptide with C1q [2] 2] activation of C4 by A4-beta peptide [3] 3] complement activation by tau [4] b) upregulation of C-reactive protein in CSF [5] c) hyperinsulinemia provokes increases in brain inflammation & beta amyloid [11] d) increased astrocyte nicotinic receptor alpha7 in hippocampus & entorhinal cortex associated with inflammatory mechanisms e) TNF-alpha upregulation may hasten cognitive decline [15] - TNF-alpha is produced by glia, neurons - TNF-alpha regulates synaptic communication - effect in the hippocampus [15] f) higher plasma levels of IL-12 p70 in cognitively intact older adults associated with - less cognitive decline in persons with significant burden of beta-amyloid - fewer neurofibrillary tangles [31] g) higher plasma levels of IFN-gamma in cognitively intact older adults associated with slower cognitive decline independent of beta-amyloid burden [31] h) CD33 may be a microglial on-off switch, activating microglia as part of an inflammatory pathway sensing brain injury as an infection [39] - microglia may mistake early Alzheimer's disease as an infection [39] i) progression of AD in the middle temporal gyrus occurs in 2 phases - an early phase with a slow increase in pathology - presence of inflammatory microglia & reactive astrocytes - a loss of somatostatin-positive inhibitory neurons - a remyelination response by oligodendrocyte precursors - a later phase - exponential increase in pathology - loss of excitatory neurons - loss of Pvalb-positive & VIP-positive inhibitory neurons [44] 6) generation of reactive oxygen species (hypothesis) a) 24-OH cholesterol 1] membrane turnover 2] upregulation of apolipoprotein E & other genes 3] toxicity attenuated by peroxisome proliferators [6] b) up-regulation of redox-modulated transcription factors [7] c) alleles of apo E allegedly have different antioxidant capabilities in the order of E2 > E3 > E4 [9] d) oxidation of UCHL1 Met & Cys - UCHL1 found associated with neurofibrillary tangles e) MAO-B activity increases with ages & is further increased in AD, possibly increasing reactive oxygen species [14] f) diminished expression of REST in prefrontal cortex of patients with mild cognitive impairment or AD [20] 7) neurotransmitter deficits occur secondary to neuronal injury a) acetylcholine [1] b) norepinephrine c) serotonin d) substance P e) GABA 8) neurons may enter cell cycle arresting in G2 phase prior tocell death [10] 9) humanin may inhibit neurofibrillary pathology, toxicity of beta-amyloid, interactions of APP, neuronal apoptosis 10) ECE2 may limit beta-amyloid peptide accumulation in brain & is down-regulated in inferior parietal lobe of patients with Alzheimer disease (at protein level) 11) other molecules implicated in pathology of AD a) retromer complex b) CAT53/PNUTS c) nicotinic acetylcholine receptor d) NDRG2 e) ubiquitin C-terminal hydrolases (?) f) ADAMTS4 g) higher plasma leptin associated with lower risk of AD [16] h) neurogranin (absence of in dendrites) i) BPTF (FALZ) re-expression of fetal protein j) HERPUD1 interacts with PSEN1 & PSEN2 & is present in activated microglia in senile plaques (normally expression in the brain is restricted to neurons & vascular smooth muscle cells) k) UBXN4 accumulates in Alzheimer disease-afflicted brains l) over expression of C20orf203 (human-specific protein?) m) clusterin may play neuroprotective role [17] n) enhanced expression of REG1A-related transcripts & intraneuronal accumulation of REG1A-like proteins o) loss-of-function mutation in ABCA1 (present in 1:500 individuals) [24] p) RBFOX1 localizes around amyloid plaques & reduced expression of RBFOX1 correlates with higher amyloid-beta burden & greater cognitive impairment in preclinical & early Alzheimer's disease [27] q) rare coding variant in ABI3 is associated with late-onset Alzheimer's disease - deletion of ABI3 significantly increases beta-amyloid plaques, & decreases microglia clustering around the amyloid plaques [37] r) alpha-endosulfine expression is increased in patients with Alzheimer's disease (see Comparative biology section) [38] s) misfolded proteins including TDP43, amyloid-beta, PHF-tau, & alpha-synuclein appear associated with cognitive impairment that typically progresses to severe dementia [28] t) epigenetically regulated MGMT expression may be involved in pathogenesis of AD, especially in women [41] t) proteins implicated in Alzheimer's disease may be found by analysis of proteome from brain, CSF & plasma [32] 12) induced pluripotent stem cells (iPSC) a) induced from fibroblasts, processed into neurons b) iPSC neurons from familial AD or sporadic AD patients 1] secrete more beta-amyloid[1-40] than controls 2] contain more active GSK3B than controls 3] contain higher phospho-tau/tau ratio than controls 4] APP beta-secretase reversed these differences [18] 13) changes in blood-based metabolites involved in energy metabolism occur 10 years before diagnosis of Alzheimer's disease [33] - low levels of branched-chain amino acids & omega-3 fatty acids - high levels of glucose, citrate, acetone, beta-hydroxybutyrate, & acetate - higher fasting serum glucose levels are associated with lower regional cerebral metabolic rates for glucose in brain regions associated with AD (precuneus/ posterior cingulate, parietal cortex, prefrontal cortex, & occipital cortex) [19] 14) blood-based biomarkers of Alzheimer's disease* show different dynamics of change after cardiac arrest [42] - an increase of plasma p-tau 24 hours after cardiac arrest suggests ischemic brain injury may release p-tau from interstitial fluid & CSF vs chronic neuronal injury resulting in increases in plasma NfL & plasma total-tau - delyed increases in plasma beta-amyloid after cardiac arrest suggest activation of amyloid processing in response to ischemia 15) chronic mild cerebral ischemia may play a role in Alzheimer's disease [42] via associations between cerebral blood flow, vascular health, & tau pathology driven in part by beta-amyloid burden [29] * see laboratory evaluation of Alzheimer's disease Comparative biology: - in mice genetically engineered to produce large amounts of microtubule-associate protein tau, mice that produced apoE4 developed markedly more deposits of tau, greater brain atrophy, & greater brain inflammation than did mice that made apoE2 or apoE3; mice that made no apoE protein were protected - inflammatory cytokines produced by microglia from apoE4 producing mice implicated - dynamin-1-like protein may play a role in NLRP3 inflammasome activation via inhibition of hexokinase-1 & glycolysis resulting in oligodendrocyte degeneration & white matter changes in mice [30] - alpha-endosulfine is an endogenous ligand of the ATP-sensitive K+ channel in mice & negatively regulates neprilysin-catalyzed proteolytic degradation of beta-amyloid; expression is increased in mouse models for Alzheimer's disease & in patients with Alzheimer's disease [38]

Related

A4 amyloid peptide; beta-peptide amyloid precursor protein (APP) or A4/beta amyloid precursor protein apolipoprotein E (APOE) microtubule-associated protein tau (neurofibrillary tangle protein, paired helical filament-tau, PHF-tau, MAPT, MTBT1, m-tau, mtau) oxysterol; hydroxysterol presenilin-1; PS-1; EC=3.4.23.-; protein S182; contains: presenilin-1 NTF subunit; contains: presenilin-1 CTF subunit; contains: presenilin-1 CTF12; PS1-CTF12 (PSEN1, AD3, PS1, PSNL1) presenilin-2; PS-2; STM-2; E5-1; AD3LP; AD5; contains: presenilin-2 NTF subunit; contains: presenilin-2 CTF subunit (PSEN2, AD4, PS2, PSNL2, STM2)

Useful

pathologic mechanisms in Alzheimer's disease

Specific

neurotransmitter pathology Alzheimer's disease

General

pathology of Alzheimer's disease (AD)

Database Correlations

Kegg hsa/hsa05010

References

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