Lecture 44 Flashcards
AD is the major cause of dementia
2:1 female:male
Environmental risk factors of AD
Age
Low educational level
Reduced mental activity in late life
Reduced physical activity in late life
Risk for vascular disease
Head injury
AD pathophysiology
amyloid plaques and neurofibrillary tangles
Amyloid plaques
extracellular
consist of amyloid-B peptide (AB)
Neurofibrillary tangles
intracellular
consist of hyperphosphorylated tau
Progression of AD neuropathology
Neuropathology primarily affects areas of higher cognitive function:
entorhinal cortex (memory formation/consolidation)
hippocampus (memory formation/consolidation)
basal forebrain cholinergic systems (learning)
neocortex (memory, learning, cognition)
Amyloid plaques, neurofibrillary tangles, and synapse loss
Synapse loss results in reduced levels of neurotransmitters–especially acetylcholine, but also serotonin, norepinephrine, and dopamine
Which is the key pathogenic molecule: AB or tau?
Genetic evidence suggests a key role for AB:
Trisomy 21 is associated with an AD-like phenotype in the 4th decade of life, and the APP GENE IS LOCATED ON CHROMOSOME 21
Mutation in the gene encoding presenilin proteins involved in cleaving AB from APP are linked to early onset AD
Production of AB peptide from APP
AB peptide is released from the transmembrane amyloid precursor protein (APP) by the activity of B-secretase (BACE1) and y-secretase
Mutations in the APP gene favor cleavage by B- or y-secretase, resulting in the production of more AB42 relative to AB40
Mutations in the gene encoding presenilin-1 or presenilin-2 which are components of the y-secretase complex, alter APP cleave by y-secretase resulting in more production of AB42 than AB40
Effects of AB aggregation on tau pathology
Kinase activation–> tau hyperphosphorylation–> neurofibrillary tangles–> disruption of cytoskeleton axonal trafficking
Neurofibrillary tangle formation results in cytoskeletal defects
In unhealthy areas where tangles have accumulated, the cytoskeletal tracks are disrupted and disorganized, resulting in defects in axonal transport that lead to synaptic dysfunction
Effects of AB aggregation on microglial activation
activated microglia release proinflammatory cytokines that cause neuroinflammation
activated microglia also release reactive nitrogen species and reactive oxygen species that cause oxidative stress
Impact of ApoE genetics on AD risk
Individuals with 1 or 2 ApoE4 alleles have an increased risk of AD, whereas inheritance of the Apoe2 allele decreases the risk
Summary of AD risk factors and pathogenic mechanisms
SLIDE 17
Donepezil
specific, reversible inhibitor of acetylcholinesterase
