Alzheimers

Question 1

What plaques develop

Answer 1

Amyloid Beta

Question 2

What do solute AB do

Answer 2

Increase glutamate release and change synaptic transmission

Question 3

What enzymes act on amyloid precursor protein

Answer 3

alpha secretase
b secretase
y secretase

Question 4

What does a secretase produce

Answer 4

sAPP. Non amyloidgenic

Question 5

what does b/y-sec make

Answer 5

AB 40 or AB42

Question 6

Pathology of AB

Answer 6

Aggregation esp. AB42
Lack of clearance
Oligomer
Amyloid Plaques
Inflammation, oxidative stress
LTP impairment from AB

Question 7

Tangles pathology

Answer 7

Oligomers activate kinases
Kinases convert tau to tau PPP
Tau PPP causes neurofibrillary tangles

Question 8

Other hypotheses for AD

Answer 8

Failure of autophagy
Loss of Ca homeostasis due to excitotoxicity
Inflammation - injury causes disease, chronic inflam state
Oxidative damage

Question 9

Reasons to doubt AB hypothesis

Answer 9

Accumulation of AB high plaque load in rats and humans doesnt = Alzheimers
When plaque load reduced by immunotherapy, no improvement

Question 10

Percentage of patients with high plaque load but no AD

Answer 10

25%

Question 11

Limitations of mouse model for AD (2)

Answer 11

Mice do not get tau tangels despite plaque load

Mice overexpress TREM2, which increases phagocytosis

Question 12

Microglia actions around AB

Answer 12

They cluster around synapses with a high plaque load, and remove them to save the axon

Question 13

What is tau normal function

Answer 13

Part of microtubules that transport materials down axons

Question 14

What is tau phosphorlayed by

Answer 14

GSK-35

Question 15

What does phosphorylated tau do

Answer 15

Dissociates from microtubules and becomes part of paired helical filament
Helical filaments then can aggregate, causing neurofibrillay tangles
Can impair axonal transport

Question 16

What mutaitons cause Familiar AD

Answer 16

APP
PSEN1
PSEN2

Question 17

What do PSEN1/2 muations do

Answer 17

Cause an increase in y secreatase activity
Increases plaques
Change AB40:42 ratio

Question 18

Pathology cause of FTD

Answer 18

Tau tangles only

Question 19

Risk genes associated with sprodratic AD

Answer 19

Apolipoprotein E4

TREM2

Question 20

What is apolipoprotein E4

Answer 20

Lipid transport protein that facilitates the cleaving of oligomers

Question 21

Risk of getting AD with homozygous for AE4

Answer 21

90%

Question 22

What does TREM2 do

Answer 22

expressed on microglia

contributes to phagocytic pathways to remove plaques

Question 23

What neruons are especially lost in AD

Answer 23

Cholinergic in basal forbrain nuclei

Question 24

Drugs used to treat AD (4)

Answer 24

Cholinesterase inhibtiors - Donezepil
Aducanumab
Memantine
Risperidone (for agression)

Question 25

Donepezil mechanism of action

Answer 25

Blocks cholinesatase, increase ACh levels

Question 26

Donepzil usefulness - 3

Answer 26

Slight improvement in MMSE (1 point) Prescribed early in AD No effect on overall decline

Question 27

Aducanumab mechasim

Answer 27

Binds to AB, so microglia clear it away PEt scans show reduction in plaques No improvements in cogntition

Question 28

Memantine mechanism

Answer 28

NMDA R weak antagonsit | Blocks excess glutamate, stabilising signals from overactive NMDA activation

Question 29

Memantine useful and side effects 4

Answer 29

Mild cognitive improvement | Side effects of headache, drowsiness, hypertension, shortness of breath

Question 30

Risperidone use

Answer 30

For agitation and agression seen in AD