Alzheimer's Disease Flashcards
What are the physiological roles of astrocytes?
Provide nutrients for neurons
Digest parts of dead/excess neurons
Regulate neuronal firing - NT uptake
What are the physiological roles of oligodendrocytes?
Insulate axons with myelin - increase AP conduction speed
What are the physiological roles of microglia?
Resident immune cells
Clear debris and dead cells
Name the top 3 neurodegenerative diseases
1st - stroke
2nd - AD
3rd - PD
What are the main symptoms of AD?
Short term memory loss
Confusion
Language difficulty
What are the leading causes of death for men and women in the UK?
Women - AD
Men - CVD
How are global AD rates changing and why?
Increasing
As increasing life expectancy
Where is the largest increase in AD rates expected and why?
LMICs
Largest projected increase in life expectancy
Which enzymes cleave APP to form AB?
Beta- then gamma-secretase
Which familial AD genes are linked to AB formation?
APP
PSEN1
PSEN2
What is the largest AD risk factor?
Age
What are the stages of AD development?
AB plaques -> tau tangles -> brain structure changes -> memory impairment
What are the common pathways in ageing and AD?
Nutrient pathways
Autophagy and proteasome - proteostasis
Inflammation
How is autophagy and proteasome function altered in both ageing and AD?
Impaired
What drives inflammageing?
Increased microglia
What is the second largest AD risk factor?
T2D
How does insulin resistance affect cognitive decline?
Increases
How is glucose metabolism altered in AD?
Decreased
What is the effect of upregulating glucose metabolism in a Drosophila AD model?
Improves symptoms
What is the evidence for impaired autophagy in AD?
Autophagosome accumulation
What is the evidence for impaired UPS in AD?
Decreased proteasome degradation efficiency
Increased ubiquitinated aggregates
How can AB and tau affect UPS?
Inhibit proteasome
Which common AD risk variants are involved in inflammation and microglia?
TREM2
CD33
What is the effect of prolonged microglial activation?
Neuronal damage
What is the key feature of C. elegans AD model and how does this compare to WT ageing?
Increased paralysis with ageing
AB expression increases paralysis likelihood
What is the key feature of Drosophila AD model and how does this compare to WT ageing?
Slight decrease in climbing ability with ageing
AB expression in adult neurons only - further decreases climbing ability
What is the effect of AB expression in mouse brains?
Worsens Morris watermaze performance - impaired learning and memory
What is the effect of crossing an AB-expressing mouse with an IGF receptor mutant (decreased insulin signalling) mouse and what does this suggest?
Offspring had better Morris watermaze performance than AB-expressing - but lower than WT
Decreasing insulin signalling increases learning ability
What is the effect of crossing an APP mutant mouse with an mTOR KO mouse and what does this suggest?
Offspring had improved Morris watermaze performance - to same level as WT
TOR deletion increases learning
How does metformin act?
Activates AMPK
What is the effect of metformin on WT animals?
Extends lifespan
What is the effect of metformin in AB-expressing Drosophila and what does this suggest?
Improves climbing
AMPK activation improves AB pathology
What is the effect of dietary restriction on AB-expressing Drosophila and what does this suggest?
No improvement to climbing ability
DR extends lifespan but does not affect AB pathology
What is the key point for the idea that age causes AD and the incidence increase is not just an effect of time?
Modulating age-related pathways affects AD development
