Alzheimer's Flashcards
AD symptoms
- memory loss (especially recent memories)
- 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 of AD
- Age
- Low educational level
- Reduced mental activity in late life
- Reduced physical activity in late life
- Risks for vascular disease
- Hear injury
AD neuropathology
- loss of brain volume
- amyloid plaques and neurofibrillary tangles
- synapse loss
Amyloid plaques
extracellular; consist of amyloid-beta peptide (Abeta)
Neurofibrillary tangles
intracellular; consist of hyperphosphorylated tau
Neuropathology primarily affects which areas of high cognitive function?
- Entorhinal cortex
- Hippocampus
- Basal forebrain cholinergic systems
- Neocortex
- Nucleus basalis
A striking feature of neurons with neurofibrillary tangles and neurons in the vicinity of amyloid plaques is
destruction of synapses
Synapse loss results in
- reduced levels of neurotransmitters - especially acetylcholine, but also serotonin, norepinephrine, and dopamine
- dysregulated glutamate -> excess excitotoxicity and neurotoxicity
Genetic evidence that suggests a key role for Abeta?
- Mutations in the gene encoding the Abeta precursor protein, APP, are linked to early onset AD
- Trisomy 21 is associated with an AD-like phenotype, and the APP gene is located on chr 21
- Mutations in the gene encoding presenilin proteins involved in cleaving Abeta from APP are linked to early onset AD
Abeta peptide is released from
the transmembrane amyloid precursor protein (APP) by the activity of beta-secretase (BACE1) and gamma-secretase
Cleavage of APP by alpha-secretase in the middle of the Abeta segment releases
a non-amyloidogenic (non-toxic) fragment
Mutations in the APP gene favor
cleavage by beta- or gamma-secretase, resulting in the production of more Abeta or more Abeta42
What do mutations in the gene encoding presenilin-1 or presenilin-2 (PSEN1 or PSEN2) do?
alter APP cleavage by gamma-secretase, resulting in the production of more Abeta or more Abeta42
Abeta aggregation is thought to promote
tau hyperphosphorylation, leading to neurofibrillary tangle formation, cytoskeletal anomalies, and disruption of axonal trafficking
What is Entresto?
Valsartan + Sacubitril: new CHF drug
What is the concern about Entresto?
It is a Neprilysin inhibitor and there’s concern that inhibitors of Neprilysin could contribute to AD
Neurofibrillary tangle formation results in
cytoskeletal defects
What happens in unhealthy areas of the brain where tangles have accumulated?
the cytoskeletal tracks are disrupted and disorganized, resulting in trafficking defects and synaptic dysfunction
Abeta is thought to induce neurotoxicity indirectly by
triggering microglial activation, a process that is probably aimed at clearing amyloid from the brain
Activated microglia release
- pro-inflammatory cytokines (PGs, interleukins, TNF-alpha) that cause neuroinflammation
- reactive nitrogen species and reactive oxygen species that cause oxidative stress
CV risk factors in AD
- elevated LDL and decreased HDL increase AD risk
- vascular disease may accelerate AD pathogenesis (decreased nutrient delivery to the brain, decreased Abeta clearance, increased Abeta accumulation)
How does diabetes increase the risk of AD?
defects in insulin signaling may lead to accumulation of toxic glucose metabolites in the brain, decreased Abeta clearance
ApoE responsible for
transporting cholesterol in brain (LDL); defects in cholesterol metabolism may alter membrane structure and function, which in turn affects Abeta deposition
Three ApoE isoforms
ApoE2, ApoE3, and ApoE4
Significance of individuals with one or two ApoE4 alleles?
One or two ApoE4 alleles increase the risk of AD
Significance of individuals with an ApoE2 allele
decreases the risk of AD
Cholinesterase inhibitors block
The conversion of acetylcholine to acetic acid and choline; thereby compensating for the loss of acetylcholine that results from the degenration of cholinergic nerve terminals in AD
Cholinesterase inhibitors
- Donepezil (Aricept)
- Rivastigmine
- Galantamine
Donepezil (Aricept)
specific, reversible inhibitor of acetylcholinesterase
Rivastigmine
inhibits acetylcholinesterase and butyrylcholinesterase
Galantamine
selective, reversible inhibitor of acetylcholinesterase and enhances the action of acetylcholine on nicotinic receptors (increases acetylcholine release from cholinergic neurons)
Memantine
NMDA antagonist that blocks glutamatergic neurotransmission via a noncompetitive mechanism
Glutamate is an
excitatory neurotransmitter that is involved in long-term potentiation, a neuronal mechanism required for learning and memory
Excess glutamate signaling leads to
excitotoxicity, a mechanism that can result in neuronal death
Candidate agents that target Abeta generation
beta and gamma-secretase inhibitors
Molecules that modulate Abeta generation or aggregation, including cholesterol or ApoE
statins and bexarotene
Candidate agents that target Abeta aggregation
inositol, polyphenols [resveratrol], peptides
Candidate agents that target Abeta clearance
vaccines, Abeta antibodies
Candidate tau kinase inhibitors
lithium, valproate
Candidate agents that reduce inflammation or oxidative stress
NSAIDs, dietary antioxidants [Vitamin E, polyphenols]
Florbetapir
radiolabeled agent that binds beta-amyloid, visualized by PET scanning
Limitation of florbetapir/PET scan
does not establish AD diagnosis (amyloid in other diseases could also be detected)
Non-AD dementias
- Vascular dementia
- Dementia with Lewy bodies (DLB)
- Frontotemporal demena - Pick’s disease
Common initial presentation of vascular dementia
impaired judgment or executive function
Vascular dementia occurs as a result of
brain injury, associated with vascular disease or stroke
The nature of deficit in thinking or physical function in vascular dementia is determined by
location of the brain injury
Dementia with Lewy bodies
combination of cognitive decline and parkinsonian symptoms; cognitive decline more prevalent at disease onset than for PD
Core diagnositic feature of dementia with Lewy bodies
visual hallucinations
Neuropathology of dementia with Lewy bodies is characterized by
the presence of cortical Lewy bodies
Frontotemporal dementia (Pick’s disease)
disinhibited behavior, poor impulse control, antisocial behavior, disturbances in executive functioning
Neuropathology of Pick’s disease is characterized by
presence of tau accumulations (Pick’s bodies)
