Alzheimer's

Question 1

Common mechanism of action…alz?

Answer 1

Increase ab42

Question 2

Where does ab42 come from?

Answer 2

b-amyloid precursor protein APP

Question 3

What is APP?

Answer 3

A large ubiquitously produced protein in mammalian cells - transmembrane protein - and processed by several possible enzymatic cleavages

Question 4

Possible extracellular cleavages of APP

Answer 4

alpha secretase

beta secretase

Question 5

Transmembrane cleavage of APP

Answer 5

gamma secretase

Question 6

Where does AB42 come from?

Answer 6

beta secretase –> gamma secretase

action on beta amyloid precursor protein (APP)

Question 7

APP processing… what is favored pathway?

Answer 7

alpha secretase –> gamma secretase

Question 8

APP processing,…what pathway leads to AB40 and AB42?

Answer 8

beta secretase –> gamma secretase

Question 9

4 mutations that lead to increased AB42?

Answer 9

Chromosome 21 (app)
Chromosome 14 (presenilin 1)
Chromosome 1 (presenilin 2)
Apolipoprotein E4 polymorphism (chormosome 19) -- via decreased clearance

Question 10

Mutated gamma secretase increases?

Answer 10

AB42 production

Question 11

Four genetic factors have been identified that predispose to alzheimer’s by affecting beta amyloid phenotype. Which of these mutations acts by increasing the production of ALL beta amyloid proteins?

Answer 11

APP mutations (chromosome 21)

Question 12

Cause of ApoE e4 Alz manifestation?

Answer 12

Decreased AB clearance

Question 13

Potential interventions

How could we reduce production of AB42?

Answer 13

Modulate secretase activity

Disrupt beta secretase in some way?

Question 14

Potential interventions

How could we increase AB42 clearance?

Answer 14

Cholesterol/statins?

Question 15

Potential interventions

How could we decrease AB42 toxicity?

Answer 15

Decrease oligimerization / protect mitochondria?

Question 16

Potential interventions

How could we decrease oxidative injury?

Answer 16

Chelate divalent metals?

Question 17

Potential interventions

How could we decrease inflammatory response?

Answer 17

NSAIDS, steroids

Question 18

Potential interventions

How could we decrease damage to nuerons?

Answer 18

memantine

Question 19

Potential interventions

How could we compensate for neuronal dysfunction

Answer 19

Donepezil

Question 20

How could we decrease production of AB42 by modulating secretase activity?

Answer 20

Decrease beta secretase

Decrease gamma secretase

Question 21

What does presenilin 1 code for?

Answer 21

gamma secretase (maybe)

Question 22

How could we increase AB clearance?

Answer 22

Somehow use ApoE dependent clearance?

Question 23

ApoE4 (+) increased risk?

Answer 23

15–>29%

Question 24

ApoE4 (-) decreased risk?

Answer 24

15–>9%

Question 25

Protective allele?

Answer 25

ApoE2

Question 26

Risk factors outside genetics?

Answer 26

``` Hypertension diabetes smoking cholesterol obseity ```

Question 27

Prevention

Answer 27

Move and weight train :)

Question 28

Tau

Answer 28

Protein involved in nuerofibrillary tangles