Week 4- Alzheimer's Disease - Pathophysiology + genetics Flashcards
what is the pathophysiology/pathophysiology and of Alzheimer?
-brain is smaller due to atrophy in cerebral cortex and hippocampus. There has been a loss in size therefore loss in brain matter
- 15-20% decrease in hippocampus volume in mild disease
-Plaques (extracellular found between cells) containing β-amyloid
peptide
• Protein misfolding and aggregation now
considered pathogenic in many
neurodegenerative diseases
-Intra-neuronal neurofibrillary tangles composed
primarily of hyperphosphorylated tau protein
-Functional losses in cholinergic, GABAergic and
monoaminergic transmitter systems
what is the hippocampus’ function? damage ?
- for memory in the brain
- symptoms of Alzheimer will come after the damage to the hippocampus
what are the beta amyloid? produced?
-β-amyloid (Aβ) is a 36-43 αα peptide produced from amyloid
precursor protein (APP) by the action of proteases called secretases
-APP is a large transmembrane glycoprotein (770 αα long)
The function of APP is not fully elucidated
• Found in neuronal and non-neuronal cells
• Cleavage part of the physiological mechanisms
- Transcriptional regulation
- Growth factor function - Role in synaptic transmission
what is amyloid precursor protein cleaved by?
APP is cleaved by α, β and γ- secretases α-secretase produces soluble APP (sAPP) • can then be cleaved by γ-secretase Cleavage by β- and γ-secretase leads to production of β-amyloid (Aβ) - toxic • Aβ40 and Aβ42 are produced • Both are found in plaques • Aβ40 is most abundant • Aβ42 is most insoluble and most amyloidogenic • Mutations in APP increase proportion of Aβ42 • Mutations in presenilin (catalytic part of the γsecretase complex) increase γ-secretase activity
how are the amyloid plaques made?
why are the soluble amyloid beta oligmers a problem for neurons?
-affect signalling through the NMDA receptor causing synaptic dysfunction, long term pertentiation, neuronal cell death is possible
what affefct does the plaques-associated protein
(apolipoproteins etc) incorporated into
fibril to produce extracellular plaque have on the neirons?
-Inflammatory response (microglial activation; cytokine release) -Mitochondrial damage -Oxidative stress →Neuronal cell death
Direct cytotoxic effects
what are neurofilrillary tangles?
- In AD Tau becomes hyperphosphorylated
- Tau normally stabilises microtubles
- Aggregates to form paired helical filaments
- Microtubules depolymerise
- Loss of axonal transport
- Neuronal cell death
what is the acetylcholine pathways like? different types
Widely distributed Nucleus basalis projects to cortex Septal nuclei project to hippocampus • Role in memory Brainstem to thalamus • Motor control Cholinergic interneurons in the striatum involved in control of movement Also roles in arousal (wakefulness) and reward pathways (nicotine addiction)
what are the neurochemical changes that occur in the acetylcholine pathways in alzhemiers?
Post mortem brain tissue demonstrates selective
loss cholinergic neurons in basal forebrain (nucleus
basalis projecting to cortex) and hippocampus
(from septal nucleus) - Cognition, learning, memory
Reduced choline acetyltransferase activity (50-90%
decrease) and other markers (AChE, choline
transport) in hippocampus and cortex. Decreased
nicotinic receptor density in the cortex.
ACh content decreased.
what is the genetic basis of early onset <60yrs of Alzheimer? mutation
-Early onset (<60y) accounts for approx. 5% of cases of -ADTrisomy 21 (Down’s syndrome) predisposes to AD APP is on Chromosome 21 -Key mutations causing early onset AD are seen in: -APP Causes APP cleavage favouring Aβ42 production -Presenilin (PSEN1 and PSEN2) Component of γ-secretase Mutation increases Aβ42 production Presenilin 1 (PSEN1) Most common mutation Columbian families with early onset AD -Tau mutations Increased phosphorylation
what is the genetic basis of late onset >60yrs of Alzheimer? mutation
-Occurs after the age of 60 years
- majority of cases
-There are 4 variants of the -ApoE gene (ApoE1-4)
-Lipid-binding lipoprotein
-Involved in transport of lipids
-APOE4 expression is strongly linked with the risk of
developing AD
Carrying 2 APOE4 alleles gives the highest risk
- APOE2 reduces the risk
-Apolipoprotein is found in the plaques
-Role in plaque clearance
what does carrying the APOE4 variant do?
- increases the risk
- less effective in clearing the amyloid beta so more plaques will accumulate increasing the pathophysicology pathways down stresam of it leading to neuronal death
what does carrying APOE2?
-DECREASE RISK
