Lecture 11: AD Microglia Flashcards
What is the role of microglia in AD?
Many AD risk genes are highly expressed by microgliaa and often have poor mouse homologues.
They can be differentiated from pluripotent stem cells and play the following roles:
- immune survielance
- maintain neuronal homeostasis
- turnover of myelin
- respond to brain injuries
- clear unwanted extracellular aggregates (such as amyloid)
- regulate synaptic plasticity
- influence blood brain barrier function.
Where do microglia come from?
they arise early in development from the yolk sac (earliest hematopoietic cells).
Can human microglia be generated from induced pluripotent stem cells (IPSC) to study these AD risk genes?
iPS microglia (IMG) protocols have been developed that aim to mimic developmental ontogeny.
Are iMGs really microglia?
They are transcriptionally similar to cultured human brain derived microglia.
Mutations in TREM2 increase AD risk by ____ fold
3-4 fold
300% chance increase of developing AD
Where is TREM2 expressed?
It is only expressed in human microglia but not other brain cells.
Can iPS microglia be used to study how TREM2 affects microglial function?
Yes, we can use CRIPSR (allows us to manipulate DNA with more efficiency) to knockout the TREM2 gene
This means that the T and A are lost and a stop codon is introduced. Then see what happens.
What happens when TREM2 is knocked out?
-Lead to less fibrillar beta amyloid being phagocytosed.
This means that not enough amyloid is eaten up.
- Impaired migration to beta-amyloid producing neurons.
This means it has a harder time detecting and migrating to beta amyloid.
What does TREM2 do?
It is important in recognizing and eating amyloid and in detecting and traveling to amyloid.
What happens if we transplant human microglia into the forebrain of early postnatal (P1) immune deficient mice?
GFP expressing human microglia within the rodent brain exhibit homeostatic surveillance and respond to injury.
What about AD: Will xenotransplanted human microglia give a DAM?
iPSC micgrolia migrate toward and interact with AD pathology and exhibit pathology induced changes in protein expression.
What does TREM2 deletion do in chimeric mice?
TREM2 deletion impairs migration of human microglia to beta-amyloid plaques in chimeric mice.
The TREM2KO is not sensing that amyloid is present.
What are some other potential uses of iPSC derived human microglia?
-Transplantation of microglia for some disease?
-Drug screening to find compounds that alter microglia function in a beneficial way.
Ex. Encourage microglia to eat more amyloid.
Other uses may be to identify drugs that modulate the activation state, decrease synaptic pruning and increase beta amyloid phagocytosis.
What are the main key points of lecture 11?
-Microglial genes are strongly implicated in the “polygenic risk” of developing AD.
-Large numbers of human microglia can be generated from patient-derived and gene-edited IPSCs to enable studies of human microglial biology.
-High throughout in vitro assays to measure phagocytosis, apoptosis, migration, etc. can be used to determine the functional effects of AD associated genes in microglia.
-Long term xenotransplantation enables studies of human microglial function in vivo.
