7. Alzheimer 2

Question 1

do we know the function of APP? what is the significance of this?

Answer 1

the exact physiological function of APP is unknown –> therefore we can’t know when AB peptides are being regulated

Question 2

what is the exact hypothesis for the amyloid hypothesis?

Answer 2

decreasing AB levels will prevent AD

Question 3

what is the AT(N) system?

Answer 3

looks at the presence of amyloid, tau, and neurodegeneration in AD

Question 4

what does it mean if you are negative for all three A, T, and N?

Answer 4

no AD

Question 5

what does it mean if you are positive for A?

Answer 5

any case where A is positive = AD or probable AD even without tau and/or neurodegeneration

Question 6

what does it mean if you are negative for A?

Answer 6

any case where A is negative = no AD

Question 7

how do they measure/detect amyloid and tau?

Answer 7

PET imaging

Question 8

4 comorbidities of AD

Answer 8

1. hypercholesterolemia
2. hypertension
3. diabetes
4. smoking (oxidative stress)

Question 9

most effective protective treatment of AD

Answer 9

exercise

Question 10

6 reasons why APP may be causatively linked to AD instead of AB

Answer 10

1. inherited mutations in APP and presenilin cause familial AD
2. mutation A673T statistically protects from AD
3. APP locus duplication is sufficient for AD
4. trisomy 21 with 3 APP leads to AD at age 40, but partial trisomy 21 with 2 APP does not
5. GWAS revealed APP SNPs with increased AD risk
6. AB is toxic

Question 11

Why does “inherited mutations in APP and presenilin cause familial AD” indicate that AD is only correlated with AB?

Answer 11

• shows that APP is linked, not AB
• shows that presenilin, not necessarily its action on APP bc it cleaves many things, is linked

Question 12

Why does “mutation A673T statistically protects from AD” indicate that AD is only correlated with AB?

Answer 12

• only shows that mutation in APP is linked, not AB

Question 13

Why does “APP locus duplication is sufficient for AD” indicate that AD is only correlated with AB?

Answer 13

• only shows that mutation in APP is linked, not AB

Question 14

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?

Answer 14

there are many other genes on chromosome 21, so this statement alone only shows a correlation with AB

Question 15

why does AB being toxic not show causation?

Answer 15

bc only demonstrated in vitro, not in vivo –> never seen parts of the brain killed by AB

Question 16

do all APP mutations increase AB formation?

Answer 16

no, some increase AB42 and some don’t

Question 17

5 benefits of finding out the physiological function of APP

Answer 17

1. reveal if AB is formed when APP executes its function or not
2. assess if familial mutations in APP are loss or gain of function
3. reveal pathways involved in APP dysfunction and AB production in AD
4. develop assay for APP functionality
5. assess existing treatments and interventions relating to APP function (not AB) - may be more precise

Question 18

what types of cells is APP found in? (3)

Answer 18

1. neurons
2. microglia
3. oligodendrocytes

Question 19

5 functions of APP

Answer 19

1. intracellular domain enters nucleus to act on transcription
2. interactions pre and post synaptically to affect plasticity
3. cell-cell interactions
4. cell survival/neuroprotection
5. cue for axonal outgrowth throughout body

Question 20

what is the half life of APP? why is this strange?

Answer 20

4-6h (very short)

if it is a cell-cell interaction molecule, would not expect it to be degraded so quickly

Question 21

where is APP mostly found? where is some APP foudn?

Answer 21

intracellular –> ER, golgi, endosomes

only small part is at the plasma membrane

Question 22

what are the 2 homologs of APP?

Answer 22

1. APLP1
2. APLP2

Question 23

what do we know about the structure of APP?

Answer 23

don’t know the whole structure, only the structures of individual domains

Question 24

what types of enzymes act on APP? 6 examples

Answer 24

proteases cleave APP

1. beta/gamma-secretases for amyloidogenic processing
2. alpha-secretases for non-amyloidogenic processing
3. HtrA1, MT5-MMP, rhomboid protease RHBDL4 in ER

Question 25

what do we see in APP transgenic mice who have increased APP?

Answer 25

mice have cognitive impairment

Question 26

what type of system is APP? what does this mean?

Answer 26

HOMEOSTATIC SYSTEM
- requires specific amount of APP, too much or too little = bad

Question 27

what is the homeostatic system of APP dependent on?

Answer 27

1. immune system
2. proteostasis
3. ECM

Question 28

what does it mean for homeostatic system of APP to be dependent on ECM?

Answer 28

only specific composition of ECM gives proper function

Question 29

biased vs unbiased investigation of APP

Answer 29

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

Question 30

what does RNA-seq of APP KO fibroblasts tell us?

Answer 30

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

Question 31

APP as a drug target

Answer 31

1. What is the evidence that inhibition will cure the disease?
   - Can’t fully KO or overexpress but modulated APP will modulate disease
2. What is the evidence that the target is drugable?
   - Unknown
3. What is the evidence of selectivity?
   - APP is NOT a good target bc expressed throughout the body, likely not selective enough