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MCDB 153 > Alzhimers disease > Flashcards

Alzhimers disease Flashcards

1
Q

what are key cellular differences between normal and Alzheimer’s brain?

A

-extensive neuronal cell death
-amyloid plaques and neurofibrillary tangles

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2
Q

what regions of the brain are impacted?

A

-neocortex (sensory, perception, cognition, etc)
-hippocampus (memory)
-amygdala (emotions)
-entorhinal cortex

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3
Q

what are neuritic plaques composed of?

A

small fragment of trans-membrane protein amyloid precursor protein (APP)

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4
Q

what are neurofibrillary tangles composed of?

A

an abnormal form of tau

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5
Q

what are the 2 classes of Alzheimer’s disease?

A

-sporadic (not inherited)
-familial (inherited)

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6
Q

what are mutations that cause Alzheimers?

A

-APP
-Presenilin-1
-Presenilin-2

mutations in Tau gene cause closely related dementias

autosomal dominant mutations

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7
Q

ApoE allele

A

major influence on sporatic (ApoE2, ApoE3, ApoE4)
-recent effort to have ApoE4 as cause
-ApoE4 doesn’t inhibit lambda-secretase, allowing more beta-amyloid to be made

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8
Q

APP

A

transmembrane protein
-resides in plasma membrane
-highly expressed in synapses

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9
Q

lambda and beta secretase

A

cut protein within lipid bilayer
-results in beta-amyloid plaque
-increased APP mutations increase beta-secretase cleavage
-increase PSEN1/2 increase lambda-secretase activity

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10
Q

beta-amyloid plaques clearance (normal vs AD)

A

normal: beta-amyloid plaque clearance is equal to generation of it
AD: 30% reduction in beta-amyloid clearance

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11
Q

what kind of building block is toxic?

A

oligomers of beta-amyloid plaques
-polymers aren’t toxic

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12
Q

why do oligomers cause neuronal cell death?

A

-forming unregulated calcium ion channels
-JNK activation, Bcl downregulation
-promoting tau dysfunction

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13
Q

what is the function of tau

A

-copurifies and binds directly to MT
-suppresses MT dynamics
-initiate axon outgrowth

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14
Q

what are neurodegenerative diseases that exhibit abundant tau-positive filamentous lesions

A

-AD
-corticobasal degeneration
-FTDP-17
-Picks disease
-progressive supranuclear palsy

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15
Q

genetic linkage of Tau to FTDP-17, PSP, Picks, and CBD

A

-neuronal cell death and abnormal tau fibers
-no amyloid plaques

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16
Q

tau alternative splicing

A

fetal: 100% 3 repeat tau (doesnt stabilize MT as well)
adult: 50% 3 repeat, 50% 4 repeat (promote stability of MT) (disease=75% 4, 25% 3)

17
Q

is there a pathological relationship btwn beta-amyloid plaques and tau?

A

tau is required for beta-amyloid mediated death
-tau is downstream of beta-amyloid

18
Q

neuronal cell death pathway with APP and tau?

A

beta-amyloid induced neuronal cell death is tau dependent

19
Q

hyperphosphorylation of tau

A

in neurofibrillary tangles
-believed to be key to tau disfunction in AD

20
Q

how might alterations in tau action cause neurodegeneration?

A

Tau dissociation->NFT formation->GOF=cell death
or
aberrant MT dynamics (over/under stabilization)->LOF MT function->cell death good evidence

21
Q

what goes wrong if tau isn’t working properly?

A

MT aren’t built/stabilized properly
-axonal transport is compromised

22
Q

epothilone D

A

blood brain barrier permanent MT stabilizing drug used in cancer chemo
-lipiphilic to get across blood brain barrier

23
Q

how is nervous impacted by bad Tau

A

it is transported along pathway throughout nervous system
-with time, bad Tau increases and good tau decreases

24
Q

how does tau go from cell to cell?

A

transported via exomes

25
Q

what is used to treat AD

A

-acetylcholinesterase inhibitors (mild, moderate AD), treats symptoms

26
Q

AD vaccine

A

-inject mice with beta-amyloid, causing immune response->antibodies
-results: mice get fewer and smaller amyloid plaques
-resulted in high levels of neuro-inflammation

27
Q

what is one of the main concerns the AD vaccine?

A

getting past the blood brain barrier
-a lot of anti beta-amyloid, some could get across barrier and reduce amount of beta-amyloid in brain

28
Q

drugs that inhibit beta- and lambda-secretase

A

drugs failed with massive side effects

29
Q

what about drugs being administered too late?

A

-molecular pathology is underway long before first clinical symptoms
-some of the drugs are failing bc they are administered too late

30
Q

passive immunization

A

make monoclonal Ab against beta-amyloid plaques and infuse into patients

31
Q

anti beta-amyloid plaque monoclonal Ab

A

-aducanumab: controversially approved by FDA
-donanemab: slowed cognitive decline, effective for modterate levels of pathological tau (FDA approved)->targets plaque
-lecanemab: slowed cognitive decline (FDA approved)->targets oligomers

MCDB 153 (11 decks)

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