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NEUR0010 > AD > Flashcards

AD Flashcards

1
Q

What are the forms of tau in our brains?

A

3 or 4 microtubule binding repeats
2N4R/1N4R
1N4R/1N3R
0N4R/3R

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2
Q

What is the effect of phosphorylation on tau?

A

The ability of tau to bind to the microtubules is also controlled by its phosphorylation
• Under normal conditions, phosphorylation is a reversible process
• When tau is phosphorylated, that favours its detachment from the microtubules

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3
Q

Which type of tau is found in fetal brains?

A

3R

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4
Q

Which form of tau is more common in disease?

A

4R>3R

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5
Q

What does hyperphosphorylated tau form?

A

In AD, hyperphosphorylated tau forms abnormal paired helical filament (PHFb tau), visible by electron microscopy

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6
Q

What is the name of the amyloid phases in AD and what is the name for stages of tau progression?

A

amyloid - Thal phases

tau - Braak

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7
Q

At which tau stage do symptoms begin?

A

III

when NFT also present in limbic structures

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8
Q

Which regions have NFT in Braak stages I-II?

A

entorhinal cortex, transentorhinal cortex, hippocampus,

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9
Q

Which 3 genes are causative in AD?

A

APP
PSEN1 (part of gamma secretase)
PSEN2 (chr21)

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10
Q

Postmortem AD brains weigh on average how much less than a typical brain?

A

1/3 less

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11
Q

what are the 3 neuropathological features of AD?

A

amyloid beta extracellular plaques
tau neurofibrillary tangles
cerebral amyloid angiopathy

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12
Q

which Abeta is most aggregation prone?

A

Abeta42

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13
Q

What is the amyloidogenic path of APP processing?

A

cleavage of APP by beta secretase (instead of alpha) then gamma secretase
the gamma secretase can cleave at a number of sites so many different forms of Abeta are generated - with Abeta42 the extra aa are hydrophobic which makes it more aggregation prone

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14
Q

What are the Thal phases?

A 
Neocortex
Subcortical
Striatum, basal forebrain
Brainstem
Cerebellum

(amyloid beta plaque spread)

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15
Q

How is tau different when P’d?

A

more prone to detach from microtubules

hyperP’d tau forms abnormal paired helical filament

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16
Q

Which pathology correlates most with symptom severity?

A

spread of tau

may indicate that intrinsically linked with malfunction/neuronal death

17
Q

what do MAPT mutations cause?

A

FTD

not AD

18
Q

what is mouse evidence for the role of tau in AD?

A

If you cross an APP mutant mouse with a tau
knockout mouse, you are essentially removing
tau
• In these mice, there is no cognitive impairment
• Thus, even though the amyloid is upstream, its
effects are mediated by the presence of tau

19
Q

how many tau phosph sites identified in AD?

A

46

20
Q

why is tau phosphorylation problematic as a therapeutic target?

A

Many tau kinases exist eg GSK3beta
In mice models they seemed effective; inhibiting tau phosphorylation reduces tangles, improved cognitive deficits in preclinical mice
Kinase inhibitors are not specific and will reduce P at many sites
Phosphorylation of tau important for its normal function

21
Q

What is ApoE?

A

Mainly produced by astrocytes, transports cholesterol to neurons + probably other functions, 3 major alleles of polymorphic gene:
ApoE2 - low frequ, protects against AD
ApoE3 - most common, neutral
ApoE4 - increases risk of AD, shown to make amyloid and tau pathology worse

22
Q

What is TREM2?

A

immunoglobulin - triggering receptor on myoloid cells 2
microglial activation sites; altered microglial behaviour including response to amyloid plaques
transmembrane
can triple individual’s risk of developing AD
low frequency

23
Q

What are some issues surrounding AD research techniques?

A

Mouse models are not ecologically valid: often extreme overexpression, mice do not actually get AD, symptoms have to be interpreted and anthropomorphised.
iPSCs - reductionist, only neurons not a network. maturity - usually AD is in decades old brain, can’t be replicated with cultured neurons; late onset disease studied in fetal neurons

NEUR0010 (2 decks)

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