Exam 3: Alzheimer's and Dementia Flashcards
Ratio female:male for AD
2:1
AD symptoms
memory loss
impaired ability to learn/reason
impaired ability to carry out daily activities; confusion, untidiness
anxiety, suspicion, hallucinations
motor dysfunction can also occur in late-stage disease
Environmental risk factors AD
age
low educational level
reduced mental activity in late life
reduced physical activity in late life
risk for vascular disease
head injury
Amyloid Plaques
extracellular
consists of amyloid b peptide
Neurofibrillary Tangles
intracellular
consist of hyper-phosphorylated tau
Progression of neuropathology
plaques and tangles spreads through the cortex as the disease progresses
Effect of Neuropathology: Entorhinal Cortex
memory formation/consolidation
Effect of Neuropathology: hippocampus
memory formation/consolidation
Effect of Neuropathology: basal forebrain cholinergic systems
learning
Effect of Neuropathology: neocortex
memory, learning, cognition
Synapse Loss in AD
neurons with neurofibrillary tangles and neurons in the vicinity of amyloid plaques see the destruction of synapse
synapse loss results in reduced levels of neurotransmitters, especially acetylcholine
dysregulated glutamate –> excess excitotoxicity and neurotoxicity
Which is the key pathogenic molecule: AB or tau?
AB
mutations in the gene encoding the AB precursor protein (APP) are linked to early onset AD
Trisomy 21 is associated wit hAD like phenotype and the APP gene is located on chromosome 21
Production of AB from APP
cleavage of APP by a-secretase in the middle of the AB segment releases a non-amyloidoogenic (non-toxic) fragment
mutations in the APP gene favor cleavage by beta or gamma secretase, resulting in the production of more AB42 relative to AB40
mutations in the gene encoding PSEN1 or 2 alter APP cleavage by gamma secretase, resulting in the production of more AB42 to AB40
Effects of AB aggregation on tau pathology
AB aggregation is thought to promote tau hyper-phosphorylation, leading to neurofibrillary tangle formation, cytoskeletal anomalies, and disruption of axonal trafficking
Neurofibrillary Tangle Formation results in cytoskeletal defects
in unhealthy areas where tangles have accumulated, the cytoskeletal tracts are disrupted and disorganized, resulting in defects in axonal transport that leads to synaptic dysfunction (tau falls off)
Effects of AB aggregation on microglial activation
activated microglia release pro-inflammatory 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 one or two Apo4 alleles have an increased risk of AD whereas inheritance of hte ApoE2 allele decreases AD risk
Donepezil
specific reversible inhibitor of acetylcholinesterase
Rivastigmine
inhibits acetylcholinesterase and butyrylcholinesterase (patch or orally)
galantamine
selective, reversible inhibitor of acetylcholinesterase AND enhances the action of acetylcholine on nicotinic receptors
Cholinesterase Inhibitor MoA
block the degradation of acetylcholine thereby compensating for the loss of acetylcholine that results from the degeneration of cholinergic nerve terminals in AD
Memantine
NMDA antagonist that blocks glutamatergic neurotransmission via a noncompetitive mechanism, reduces excitotoxicity
Strategies for Disease Modifying Therapy (AD)
AB generation (beta and gamma secretase inhibitors)
AB aggregation (inositol, polyphenols, peptides)
AB clearance (vaccine, AB antibodies (aducanumab, lecanemab, donanemab)
tau kinase inhibitors (lithium, valproate)
glutamate mediated excitotoxcity (induces expression of GLT-1 transporter)
inflammation or oxidative stress (NSAIDS, dietary antioxidants)
Florbetapir
radiolabeled agent that binds beta-amyloid, visualized by PET scanning
radiolabeled agent specific for tau: 18F-Flortaucipir
