44 - Alzheimer's Flashcards
AD is the major cause of demantia
- 50-80% of dementia cases
- ___ : ___ female:male
- ___ is major factor
2:1
age
AD symptoms
- memory loss (especially ___ memories)
- impaired ability to learn
- impaired ability to carry out daily activities, confusion, untidiness
- anxiet, suspicion, ___
- ___ dysfunction can also occur in late stage
recent
hallucinations
motor
enviromental risk factors
- age
- low ___ level
- reduced ___ and ___ activity in late life
- risks for ___ disease
- ___ injury
educational
mental, physical
vascular
head
AD neuropathology:
- loss of brain ___
- ___ plaques and ___ tangles
- ___ loss
spreads though ___ as disease progresses
- volume
- amyloid, neurofibrillary
- synapse
- cortex
amyloid plaques are located ___ and consist of ___ peptide
neurofibrillary tangles are located ___ and consist of hyperphosphorylated ___
extracellularly
amyloid-B
intracellularly
tau
neuropathology primarily affects areas of higher cognitive function
- ___ cortex and ___ (memory formation/consolidation)
- basal ___ cholinergic systems (learning)
- ___ (memory learning, cognition)
- nucleus basalis (memory, attention, arousal, perception)
- entorhinal, hippocampus
- forebrain
- neocortex
amyloid plaques, neurofibrillary tangles, and synapse loss
- neurons with tangles or close to plaques get their synapses destroyed
- synapse loss results in reduced levels of neurotransmitters, especially ___ , but also serotonin, norepinephrine, and dopamine
- dysregulated ___ = excess excitotoxicity and neurotoxicity
ACh
glutamate
which is the key pathogenic molecule? AB or tau?
genetic evidence suggests ___
- mutations in gene encoding precursor protein ___ are linked to early onset AD
- gene located in chromosome ___
- mutations in gene encoding presenilin proteins involved in cleaving ___ from ___ are linked to early onset
AB
- APP
- 21
- AB, APP
prooductions of AB peptide from APP
- __ and __ secretases release AB from APP. AB __ forms fibrils better than AB40
- __ secretase cuts the middle of the AB segment and releases a non-toxic fragment
- mutations in APP gene favor ___ or ___ secretase resulting in more AB ___
- mutations in the gene encoding presenilin 1 or 2 affect ___ secretase, resulting in more AB ___
hotdogs
- beta, gamma
- 42
- alpha
- beta, gamma, 42
- gamma, 42
effects of AB aggregation on tau patho
AB aggregation is thought to promote tau ___, leading to neurofibrillary tangle formation, ___ anomalies, and disruption of axonal ___
hyperphosphorylation
cytoskeletal
trafficking
neurofibillary tangle formation results in cytoskeletal defects
in unhealthy areas where tangles have accumulated, the ___ tracks are disrupted and disorganized, resulting in defects in axonal ___ that lead to synaptic dysfunction
cytoskeletal
transport
effects of AB aggregation on microglial activation
AB is thought to induce neurotoxicity indirectly by triggering ___ activation
- activation leads to release of pro-inflammatory cytokines that cause ___
- also leads to release of reactive ___ and ___ species that cause ___ stress
microglial
- neuroinflammation
- nitrogen, oxygen, oxidative
impact of ApoE genetics on AD risk
ApoE - responsible for transporting ___ in brain
- altered function can affect AB aggregation/clearance
individuals with one or two ApoE ___ alleles have an increased risk of AD whereas inheritance of ApoE __ allele decreased AD risk
cholesterol
4
2
ApoE2 = protective
ApoE4 = increased risk
cholinesterase inhibitors
MOA: block breakdown of ___ and compensate for its loss resulting from degeneration of cholinergic nerve terminals in AD
donepezil ( ___ ) - specific reversible inhibitor of ___
rivastigmine - inhibits ___ and ___ (delivered PO or with a patch)
galantamine - selective, reversible inhibitor of ___ and enhances the action of ___ on nicotinic receptors (increases release from cholinergic neurons)
ACh
- Aricept, acetylcholinesterase
- acetylcholinesterase, butyrylcholinesterase
- acetylcholinesterase, ACh
anti-glutamatergic therapy
___ : NMDA antagonist that block glutamatergic neurotransmission via a ___ mechanism, reduces ___
combo drug: memantine ER + donepezil: ___
memantine
- noncompetitive, excitotoxicity
Namzaric
