7. Alzheimer 2 Flashcards
do we know the function of APP? what is the significance of this?
the exact physiological function of APP is unknown –> therefore we can’t know when AB peptides are being regulated
what is the exact hypothesis for the amyloid hypothesis?
decreasing AB levels will prevent AD
what is the AT(N) system?
looks at the presence of amyloid, tau, and neurodegeneration in AD
what does it mean if you are negative for all three A, T, and N?
no AD
what does it mean if you are positive for A?
any case where A is positive = AD or probable AD even without tau and/or neurodegeneration
what does it mean if you are negative for A?
any case where A is negative = no AD
how do they measure/detect amyloid and tau?
PET imaging
4 comorbidities of AD
- hypercholesterolemia
- hypertension
- diabetes
- smoking (oxidative stress)
most effective protective treatment of AD
exercise
6 reasons why APP may be causatively linked to AD instead of AB
- inherited mutations in APP and presenilin cause familial AD
- mutation A673T statistically protects from AD
- APP locus duplication is sufficient for AD
- trisomy 21 with 3 APP leads to AD at age 40, but partial trisomy 21 with 2 APP does not
- GWAS revealed APP SNPs with increased AD risk
- AB is toxic
Why does “inherited mutations in APP and presenilin cause familial AD” indicate that AD is only correlated with AB?
- shows that APP is linked, not AB
- shows that presenilin, not necessarily its action on APP bc it cleaves many things, is linked
Why does “mutation A673T statistically protects from AD” indicate that AD is only correlated with AB?
- only shows that mutation in APP is linked, not AB
Why does “APP locus duplication is sufficient for AD” indicate that AD is only correlated with AB?
- only shows that mutation in APP is linked, not AB
Why does “trisomy 21 with 3 APP leads to AD at age 40, but partial trisomy 21 with 2 APP does not” indicate that AD is only correlated with AB?
there are many other genes on chromosome 21, so this statement alone only shows a correlation with AB
why does AB being toxic not show causation?
bc only demonstrated in vitro, not in vivo –> never seen parts of the brain killed by AB
do all APP mutations increase AB formation?
no, some increase AB42 and some don’t
5 benefits of finding out the physiological function of APP
- reveal if AB is formed when APP executes its function or not
- assess if familial mutations in APP are loss or gain of function
- reveal pathways involved in APP dysfunction and AB production in AD
- develop assay for APP functionality
- assess existing treatments and interventions relating to APP function (not AB) - may be more precise
what types of cells is APP found in? (3)
- neurons
- microglia
- oligodendrocytes
5 functions of APP
- intracellular domain enters nucleus to act on transcription
- interactions pre and post synaptically to affect plasticity
- cell-cell interactions
- cell survival/neuroprotection
- cue for axonal outgrowth throughout body
what is the half life of APP? why is this strange?
4-6h (very short)
if it is a cell-cell interaction molecule, would not expect it to be degraded so quickly
where is APP mostly found? where is some APP foudn?
intracellular –> ER, golgi, endosomes
only small part is at the plasma membrane
what are the 2 homologs of APP?
- APLP1
- APLP2
what do we know about the structure of APP?
don’t know the whole structure, only the structures of individual domains
what types of enzymes act on APP? 6 examples
proteases cleave APP
- beta/gamma-secretases for amyloidogenic processing
- alpha-secretases for non-amyloidogenic processing
- HtrA1, MT5-MMP, rhomboid protease RHBDL4 in ER
what do we see in APP transgenic mice who have increased APP?
mice have cognitive impairment
what type of system is APP? what does this mean?
HOMEOSTATIC SYSTEM
- requires specific amount of APP, too much or too little = bad
what is the homeostatic system of APP dependent on?
- immune system
- proteostasis
- ECM
what does it mean for homeostatic system of APP to be dependent on ECM?
only specific composition of ECM gives proper function
biased vs unbiased investigation of APP
BIASED: we know APP is involved in collagen so we investigate APP affecting collagen
UNBIASED: unbiasedly learn about changes in APP using overexpression and KO
what does RNA-seq of APP KO fibroblasts tell us?
proactively involved in changing ECM
maybe involved in transport of ECM components and maturation through activity in golgi and ER
APP KO has increased fibronectin so APP must be negative regulator of fibronectin –> APP KO mice have stiffer brains
Therefore, APP changes ECM in brain where too little or too much APP = memory issue
APP as a drug target
- What is the evidence that inhibition will cure the disease?
- Can’t fully KO or overexpress but modulated APP will modulate disease - What is the evidence that the target is drugable?
- Unknown - What is the evidence of selectivity?
- APP is NOT a good target bc expressed throughout the body, likely not selective enough
