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PHAR 503 > 6. Alzheimer 1 > Flashcards

6. Alzheimer 1 Flashcards

1
Q

what are the 3 things to consider for a drug target?

A
  1. What is the evidence that inhibition of a protein or normalizing phenotype will cure disease?
  2. What is the evidence that the target is drugable? Can it reach and act on the protein?
  3. What is the evidence of selectivity?
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2
Q

what is dementia vs AD?

A

dementia is a general term describing impairment of memory and cognitive function

AD is a specific form of dementia with pre-symptomatic stages

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3
Q

what type of disorder is AD?

A

progressive neurodegenerative disorder

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4
Q

how many patients does AD affect worldwide?

A

35 million

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5
Q

what is impaired in AD? 5

A
  1. cognitive function
  2. spatial orientation
  3. memory
  4. language
  5. change personality
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6
Q

what are the 4 stages of AD?

A
  1. Healthy brain
  2. Preclinical
  3. Mild cognitive impairment (MCI)
  4. AD
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7
Q

describe stage 1: healthy brain

A

gradual cognitive decline with no obvious brain pathology

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8
Q

describe stage 2: preclinical

A

cognitive decline in episodic memory with no obvious brain pathology

3-4 years before MCI

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9
Q

describe stage 3: MCI

A

accelerated cognitive decline with observable brain pathology

25% of patients convert to AD

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10
Q

describe stage 4: AD

A

severe dementia, loss of life, loss of brain tissue

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11
Q

why does AD have a large socioeconomic impact?

A

the disease lasts a really long time –> 8-12 years

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12
Q

describe the brain that Alois Alzhemer observed

A

massive atrophy with less white matter

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13
Q

describe the tau fibrils we see in AD. how is this different than tau proteins we see normally?

A

irreversibly hyperphosphorylated tau proteins that form swirls

tau proteins are normally phosphorylated to protect neurons and reduce their metabolism but this is reversible

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14
Q

why is AB regarded as the causative agent of AD? what do they believe is the role of tau?

A

tau - APP/AB transgenic mice had more tau fibrils than just tau transgenic mice

tau is contributing/necessary for mediating AB toxicity

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15
Q

besides AB and tau, what is another pathological hallmark of AD? why don’t we study this very much?

A

lipid droplets/accumulation

can’t do stains or other assays as easily for lipid droplets

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16
Q

what are MoCA and MMSE?

A

Montreal Cognitive Assessment and Mini-Mental State Examination

recall 5 words, draw a clock, etc.

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17
Q

how can we detect AD pathology in the brain? is this diagnostic?

A

can do PET imaging of amyloid and/or tau fibrils

not diagnostic –> can only get definite diagnosis post-mortem bc can’t do brain biopsies so can’t monitor the disease

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18
Q

what do brain biopsies indicate?

A

the measurement of neurodegeneration

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19
Q

3 treatments for AD

A
  1. Cholinesterase inhibitors
  2. NMDA receptor antagonist
  3. aducanumab and lecanemab
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20
Q

describe the disease-modifying antibodies, aducanumab and lecanemab

A

both effectively remove plaques from the brain but detected that 40% of people had unspecific brain bleeds

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21
Q

what is a hypothesis?

A

experimentally testable proposal where the experiment will validate or disprove the hypothesis

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22
Q

describe the movement of APP through the cell before it is processed (4 steps)

A
  1. made in ER
  2. glycosylated
  3. golgi
  4. reaches cell surface for processing
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23
Q

describe the processing of APP (3 steps)

A
  1. beta-secretase cleaves above membrane, releasing the soluble ectodomain
  2. intramembrane gamma-secretase cleaves the transmembrane part and releases AB
  3. AB easily aggregates and forms plaques
24
Q

does APP processing only occur in AD patients?

A

no it is a physiological process involved in synaptic growth

25
Q

inherited vs sporadic cases of AD

A

97% of cases are sporadic
3% of cases are dominant inherited familial

26
Q

3 mutations that can be passed down in dominant inherited familial

A
  1. mutations in APP at beta-secretase cleavage site
  2. mutations in presenilin in gamma-secretase
  3. mutations in AB to cause it to aggregate
27
Q

what does APP stand for?

A

Amyloid Precursor Protein

28
Q

difference between the transmembrane APP and AB?

A

transmembrane protein is alpha helix, then becomes beta sheets when released from membrane that can terminally aggregate

29
Q

what form of AB is most toxic?

A

soluble OLIGOMERS

30
Q

describe the formation of plaques

A

monomer becomes dimers/oligomers (toxic!!!) becomes fibrils becomes plaques

31
Q

how do mutations contribute to plaque formation?

A

mutations enhance processing of APP into fibrils

32
Q

describe the hypothesis of intracellular AB peptides causing AD

A

people thought intracellular AB caused AD

if you inject intracellular AB into neurons, there is reduced long-term potentiation and learning but it is VERY non-soluble so the neuron wouldn’t function very well

33
Q

how did we find that oligomeric AB is most toxic?

A

looked at monomer+oligomer AB in cells –> caused reduced long term potentiation and learning

looked at only oligomer AB in cells –> caused reduced long term potentiation and learning, therefore oligomer is most toxic

34
Q

what is the amyloid hypothesis?

A

AB causes AD

35
Q

5 main arguments in support of amyloid hypothesis

A
  1. APP is located on chromosome 21 and trisomy 21 gives AD at age 40
  2. hereditary mutations in APP and presenilin cause early onset AD
  3. there is increased AB levels in AD from more production/retention of AB
  4. APP mutation (A673T) protects from AD
  5. AB is toxic if applied to cells
36
Q

why is the argument about trisomy 21 not a valid argument?

A

This only indicates that APP is causative to disease but AB is only associated

37
Q

why is the argument about hereditary AD not a valid argument?

A

This only indicates that APP and presenilin are causative to disease and AB is only associated

38
Q

what type of drug discovery can we use for AD drugs? why?

A

TARGET-based drug discovery –> because we understand the genes involved in APP processing and AB production

39
Q

what is the catalytically active subunit of gamma secretase?

A

presenilin

40
Q

mechanism of gamma-secretase

A

sequential cleavage mechanism cutting ~3 aa at a time off of the transmembrane part of APP

41
Q

2 AB that can be produced, which is more toxic?

A

Major: AB40
Minor: AB42 –> very sticky!!!

42
Q

type of drug when gamma secretase is used as pharmacological target

A

transition state inhibitor to block cleavage of APP

43
Q

what were the results of the gamma secretase inhibitors?

A

reduced AB in CSF –> therefore can gamma-secretase can be druggable in the human brain!

but side effects bc essentially creating a notch KO

44
Q

describe the side effects of GSIs

A

notch signaling relies on gamma secretase to clean up stuff in the membrane and is involved in development and differentiation in the intestine –> people had intestinal bleeds, skin cancer

45
Q

what happened when they tried to modify GSI? how do they evaluate whether there were side effects?

A

performed assay where you see red fluorescence when APP is cleaved and green when notch is NOT cleaved –> modified GSIs to cleave APP more than notch but still gave some GI side effects

46
Q

describe the aftermath of a study looking at rheumatoid arthritis and NSAIDs

A

analyses revealed lower rate of AD in NSAID treatment group

so people did clinical trials where AD patients were given NSAIDs –> NSAIDs didn’t help because these people had already started AD

47
Q

but why are NSAIDs still promising for AD treatment?

A

some NSAIDs affect AB42 generation –> therefore must act somewhere in APP processing

48
Q

what type of drug did NSAIDs provide the basis for?

A

2nd generation gamma-secretase modulators (GSM) –> ex. Tarenflurbil does not inhibit COX1/COX2 but did decrease AB42

49
Q

Did clinical trials of GSMs work? Why?

A

No –> too many gamma-secretase substrates, would need to test all substrates!

50
Q

are there any pharmacological therapies for AD that target AB?

A

No –> they all fail

51
Q

what is the first reason for failures of clinical trials?

A

only in 2010 did they look at biomarkers in patients and found that the increase in AB occurs 15-25 years before clinical onset
- so if you recruit AD patients and non-AD controls, you don’t know if the controls are also patients –> whole trial design is criticized

52
Q

what is a way to help clinical trials overcome the issue of AB increasing before clinical onset?

A

use children of AD patients and try to PREVENT AD

53
Q

why can we only prevent AD and not cure AD?

A

Cannot cure AD bc too many changes over a long period of time

54
Q

what is the second reason for failures of clinical trials?

A

AB may be directly correlated with the disease-causing factor but is not the cause itself –> must differentiate btwn causation and correlation

55
Q

consideration of gamma-secretase as a drug target

A
  1. What is the evidence that inhibition will cure the disease?
    - Dominant inherited mutations are in presenilin of gamma-secretase found in some AD patients
  2. What is the evidence that the target is drugable?
    - AB in CSF, can measure AB
  3. What is the evidence of selectivity?
    - Gamma-secretase is NOT a good target bc involved in so many pathways in every cell and not upregulated in disease
    - They could have predicted this if they had knocked out presenilin bc the cells would die
56
Q

consideration of AB as a drug target

A
  1. What is the evidence that inhibition will cure the disease?
    - AB is NOT a good target bc not a gene!
  2. What is the evidence that the target is drugable?
    - We have evidence that antibodies are effective to reduce AB
  3. What is the evidence of selectivity?
    - AB is NOT a good target bc AB is always present even in non-disease and we don’t know its role

PHAR 503 (10 decks)

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