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PHAR 503 > 8. Alzheimer 3 > Flashcards

8. Alzheimer 3 Flashcards

1
Q

reasons why cholesterol and vascular dysfunction is linked to AD (8)

A
  1. high serum LDL during midlife
  2. ApoE4, Trem2, ApoJ, ABCA7
  3. atherosclerosis
  4. T2 diabetes
  5. smoking
  6. hypertension
  7. hyperlipidemia
  8. obesity
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2
Q

2 genetic variants that are protective against AD

A
  1. ApoE2 variant is neutral and associated with longevity of AD and protects from cognitive decline
  2. APP mutation statistically protects from AD
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3
Q

Effect of presenilin mutation

A

usually gives early onset AD

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4
Q

Describe effect of presenilin mutation with 2 ApoE3 ChC mutations

A
  • lots of plaques and less tau but cognitively healthy
  • therefore, ChC mutation overrides AD pathology from the presenilin mutation
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5
Q

why did we look at centenarians for AD?

A

there is association of CETP variants with longevity, cognitive function, and memory in centenarians

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6
Q

lipoprotein plasma profile associated with longevity and preservation of cognitive function

A

healthy people with high HDL and almost no LDL had mutation where CETP was not spliced –> modulated age-related cognitive function

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7
Q

correlation of CETP genotype with AD/memory

A

CETP modifies the effect of memory decline with at least 1 allele of ApoE4

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8
Q

describe the memory performance of different ApoE4 and CETP variant combinations

A

ApoE4 carriers with WT CETP or heterozygous CETP mutation declined FASTER

ApoE4 carriers with homozygous CETP mutation had normal memory performance –> therefore, CETP variant overrides negative effects

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9
Q

is CETP protective in early or late AD?

A

CETP is protective in early cognitive decline in ApoE4, not protective in late stages

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10
Q

why is CETP studied extensively?

A

CETP is implicated in CVD and people want to study CVD

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11
Q

What is CETP?

A

Serum glycoprotein secreted by the liver

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12
Q

What is the role of CETP?

A

Carries CE from HDL –> LDL
Carries TAG from LDL –> LDL

Pro-atherosclerotic bc increases LDL

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13
Q

difficulty in studying CETP in mice? why does this cause problems in AD studies?

A

mice don’t express CETP and have very low VLDL and LDL

problem in many AD studies bc they ignored the fact that mice have very low LDL

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14
Q

2 hypotheses about CETP and AD and 2 research questions

A
  1. CETP activity contributes to AD
  2. CETP inhibition may delay or prevent AD onset in ApoE4 carriers
  3. How does CETP affect cholesterol distribution in a mouse?
  4. Does CETP inhibition rescue AD pathology?
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15
Q

what is the first step in investigating CETP in AD?

A

confirm a cholesterol diet induces CETP

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16
Q

experiment: confirm cholesterol diet induces CETP

A

compare humanCETP transgenic mice to WT controls

2 months old –> fed high cholesterol diet
5 months old:
- control diet had inactive CETP in liver and baseline activity in plasma
- high cholesterol diet had active CETP in liver and increased activity in plasma

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17
Q

once it was confirmed that cholesterol diet induces CETP, what is the next step?

A

look at lipoprotein profiles in hCETP transgenic mice

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18
Q

results of experiment: lipoprotein profiles in hCETP transgenic mice

A
  • HDL levels decrease a little bit with CETP on both diets
  • LDL levels increase A LOT with CETP on high cholesterol diet

Therefore, hCETP transgenic mice have humanized lipoprotein profile

19
Q

what is MALDI-IMS? how does it work (4 steps)?

A

Matrix-Assisted Laser Desorption/Ionization-Imaging Mass Spec

  1. section brain
  2. put sections on a grid with a matrix for MS
  3. ionize with a laser beam and get masses of specific molecules
  4. look at MS to see how specific mass is distributed across the brain
20
Q

what is the purpose of the matrix in MALDI-IMS?

A

protects organic tissue from laser beam

21
Q

what are the 2 ways we can confirm that CETP increases cholesterol?

A
  1. MALDI-IMS of brain lipids
  2. stain brain with filipin
22
Q

results of MALDI-IMS of brain lipids

A

CETP mice on both diets have more cholesterol –> therefore CETP increases cholesterol in the brain

23
Q

what is filipin?

A

binds cholesterol and stains it blue

24
Q

results of filipin stain

A

More cholesterol staining in CETP transgenic mice, more with high cholesterol diet

25
Q

CETP and inflammation levels in periphery vs brain

A

high CETP and inflammation in liver

high CETP and less inflammation in brain

26
Q

why do we look at integrity of BBB? how does this work?

A

to ensure that the CETP models on both diets can maintain the integrity of BBB

Inject Evans Blue into plasma (v large molecule) it will stain all tissue except for the brain bc of BBB –> if brain is blue, there is breakdown of BBB

27
Q

describe drug repurposing with CETP inhibitors

A

CETP inhibitors have been developed for CVD so now we can test for AD

28
Q

4 benefits of drug repurposing

A
  1. toxicity testing in humans already done
  2. faster progression through clinical trials
  3. saves lots of time and money
  4. adverse effects/side effects/tolerability in humans is likely known
29
Q

why should we test whether CETP inhibitors can enter the brain?

A

because AD is a disease of the brain so must be able to control CETP in brain

30
Q

experiment: can CETP inhibitor enter the brain?

A

1 IV dose of drug
- detectable levels in brain!

31
Q

what type of mice is best to use for testing CETP inhibitors in AD?

A

cross APP transgenic mice with hCETP transgenic mice and put on high cholesterol die

32
Q

experiment: CETP inhibition in plasma

A

measure CETP inhibition in plasma by measuring the amount of lipids transferred

  • WT and APP mice have no CETP activity
  • CETP and A/C mice have CETP and drug inhibits it!

Therefore, drug inhibits CETP activity and transfer of lipids

33
Q

experiment: quantification of HDL, LDL in plasma

A
  • WT and APP mice have no change in LDL or HDL
  • CETP and A/C mice have increased HDL and decreased LDL with drug

Therefore, drug and mouse model work!

34
Q

how can we measure memory performance?

A

train mouse with 2 same objects –> next day, replace with 1 new object –> measure amount of time spent investigating new object

mouse should spend more time looking at new object than something they already know

35
Q

experiment: CETP inhibitors and memory performance

  • how does this relate to centenarian studies?
A

in CETP and A/C mice with drug –> increased memory performance

therefore, in A/C, drug overrides the negative effect from APP

matches centenarian studies!

36
Q

correlation of LDL/HDL vs cognitive performance

A

increased cognition:
- increased HDL
- decreased LDL

37
Q

experiment: AB quantification in brain

A

no difference in AB levels in APP vs A/C mice and treated vs untreated

therefore, no association with AB and cognition –> DISPROVES amyloid hypothesis

38
Q

experiment: cholesterol in hippocampus

A

use filipin to measure amount of cholesterol

in CETP and A/C mice, increased cholesterol in brain

39
Q

describe cholesterol in the brain normally

A

brain has 25% of whole body cholesterol –> effluxed from brain by conversion to 24S-hydroxy-cholesterol

40
Q

why do CETP transgenic mice have more cholesterol in the brain?

A

detected lower levels of 24S-hydroxy-cholesterol –> therefore there is less cholesterol efflux from the brain and therefore high cholesterol in the brain

41
Q

3 conclusions of CETP as modulator of AD pathology

A
  1. mutating CETP can delay conversion from early to late AD, depending on ApoE4
  2. brain cholesterol levels increase in CETP transgenic mice
  3. CETP inhibitor can maintain memory
42
Q

current hypothesis about CETP as a modulator of AD pathology

A

CETP redistributes cholesterol in the brain in an UNBENEFICIAL way that interferes with something in the brain to cause impaired cognition –> CETP inhibition rescues this

43
Q

2 future directions regarding CETP as a modulator of AD pathology

A
  1. is it peripheral or central CETP?
  2. how are CETP and ApoE4 connected?
44
Q

CETP as a drug target

A
  1. What is the evidence that inhibition will cure the disease?
    - We know CETP inhibition is associated with longevity and humans with CETP deficiency have no cognitive impairment
    - SNPs, mutations, and KO in humans can tell us that cognitive performance can be maintained
  2. What is the evidence that the target is druggable?
    - CETP is in blood –> very druggable in blood
    - But unsure if CETP is druggable in brain bc hard to measure CETP activity/lipid transfer
    - We already know that many drugs can alter CETP and modify lipid profile
  3. What is the evidence of selectivity?
    - CETP is upregulated in high cholesterol diet and we know high cholesterol diet is risk factor
    - CETP is in many places so could give off-target effects BUT mostly active in plasma where drug would stay
    - + unique activity profile with pretty good evidence of selectivity

PHAR 503 (10 decks)

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