Patho of dementia/alzheimer's Flashcards
AD epidemiology
-major cause of dementia
-more females
->85yo
-mean survival 8 years after dx
AD sx
-memory loss (esp shortterm)
-impaired ability to learn/reason
-impaired ability to carry out ADLs, confusion, untidiness
-anxiety, suspicion, hallucination
-motor dysfunction can also occur late stage
Environmental risk factors of AD
-age
-low education level
-reduced mental/physical activity in late life
-risk for vasc disease
-head injury
AD neuropathology
-loss of brain volume
-amyloid plaques and neurofibrillary tangles
-synapse loss
Amyloid plaques
-extracellular
-consist of amyloid-B peptide (AB)
neurofibrillary tangles
-intracellular
-consist of hyper-phosphorylated tau
Progression of neuropathology
-plaques and tangles spread through cortex
-entorhinal cortex (memory formation/consolidation)
-hippocampus (‘’)
-basal forebrain cholinergic systems (learning)
-neocortex (memory, learning, cognition)
-nucleus basalis (memory, attention, arousal, perception)
synapse loss
-destruction of synapses in neurons w tangles and near amyloid plaques
=dec levels of NT, esp ACh but also serotonin, NE, DA
-also = dysregulated glutamate = xs excitotoxicity and neurotoxicity
Which is key pathogenic molecule: AB or tau?
-genetic evidence suggests AB
-mutations in gene encoding AB precursor protein APP are linked to early onset AD
-trisomy 21 (down’s) associated w AD-like phenotype at 40 yo and APP gene is located on chromo 21!!
-mutations in gene encoding presenilin protein involved in cleaving AB from APP are linked to early onset AD
Production of AB peptide from APP
-AB peptide released from transmembrane amyloid precursor protein (APP) by activity of B-secretase (BACE) and y-secretase
-cleavage of APP by a-secretase in middle of AB segment releases non-amyloidogenic (non-toxic) fragment
-AB generally 40-42 aa
-AB42 forms amyloid fibrils more readily than AB40
Mutations in APP gene
-favor cleavage of APP by B or y secretase
=more AB42 than AB40 (more plaques)
mutations in presenilin-1 or 2 (PSEN1 or 2) genes
-PSEN1 and 2 are components of y-secretase complex
-alter APP cleavage by y-secretase
=more AB42 to AB40
Effects of AB aggregation on tau pathoology
=kinase activation
=tau hyperphosphorylation
=tangles
=disruption of axonal trafficking
Accumulation of tangles
-cytoskeletal mincrotubule tracks are disrupted and disorganized
=defects in axonal transport
=synaptic dysfunction
Effects of AB aggregation of microglial activation
-neuroinflammation and oxidative stress
-microglial activation probably trying to clear amyloid
-activated microglia release proinflammatory cytokines (prostaglandins, IL, TNFa)
-also release reactive nitrogen species (nitric oxide and peroxynitrite) and ROS (superoxide, hydrogen peroxide) that cause oxidative stress
ApoE
-transport LSL in brain
-altered function can affect AB aggregation or clearance
Impact of ApoE genetics on AD risk
-three isoforms (ApoE2,3,4)
-ApoE4 inc risk of AD
-ApoE2 dec AD risk
slide 17 summary
slide 17 summary
Which of the following statements is TRUE?
(A) Aβ accumulation results in an inhibition of kinases that
phosphorylate tau.
(B) Interleukins contribute to synaptic loss in AD.
(C) The presence of one or two ApoE2 alleles increases the risk
of AD.
(D) Synaptic degeneration in AD triggers a loss of acetylcholine
but not dopamine.
Interleukins contribute to synaptic loss in AD
Current AD therapies
-cholinesterase inhibitors
-anti-glutamaterfic therapy
-new, anti-amyloid antibodies
Cholinesterase inhibitor drugs
-Donepezil
-Rivastigmine
-Galantamine
cholinesterase inhibitor MOA
-block enzymatic reaction shown on slide 20
-compensate for loss of ACh that results from degeneration of cholinergic nerve terminals in AD
cholinesterase
