AD Flashcards
What are the forms of tau in our brains?
3 or 4 microtubule binding repeats
2N4R/1N4R
1N4R/1N3R
0N4R/3R
What is the effect of phosphorylation on tau?
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
Which type of tau is found in fetal brains?
3R
Which form of tau is more common in disease?
4R>3R
What does hyperphosphorylated tau form?
In AD, hyperphosphorylated tau forms abnormal paired helical filament (PHFb tau), visible by electron microscopy
What is the name of the amyloid phases in AD and what is the name for stages of tau progression?
amyloid - Thal phases
tau - Braak
At which tau stage do symptoms begin?
III
when NFT also present in limbic structures
Which regions have NFT in Braak stages I-II?
entorhinal cortex, transentorhinal cortex, hippocampus,
Which 3 genes are causative in AD?
APP
PSEN1 (part of gamma secretase)
PSEN2 (chr21)
Postmortem AD brains weigh on average how much less than a typical brain?
1/3 less
what are the 3 neuropathological features of AD?
amyloid beta extracellular plaques
tau neurofibrillary tangles
cerebral amyloid angiopathy
which Abeta is most aggregation prone?
Abeta42
What is the amyloidogenic path of APP processing?
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
What are the Thal phases?
Neocortex Subcortical Striatum, basal forebrain Brainstem Cerebellum
(amyloid beta plaque spread)
How is tau different when P’d?
more prone to detach from microtubules
hyperP’d tau forms abnormal paired helical filament
Which pathology correlates most with symptom severity?
spread of tau
may indicate that intrinsically linked with malfunction/neuronal death
what do MAPT mutations cause?
FTD
not AD
what is mouse evidence for the role of tau in AD?
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
how many tau phosph sites identified in AD?
46
why is tau phosphorylation problematic as a therapeutic target?
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
What is ApoE?
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
What is TREM2?
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
What are some issues surrounding AD research techniques?
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
