A new study by researchers in the Picower Institute for Learning and Memory at MIT demonstrates how a rare but potent genetic mutation that alters microglia, can give people as much as a three-fold greater risk of developing Alzheimer’s disease. The study reveals that microglia with mutant TREM2 protein reduce brain circuit connections, promote inflammation, and contribute to Alzheimer?s pathology in other ways.
The findings are published in Glia in an article titled, “iPSC-derived microglia carrying the TREM2 R47H/+ mutation are proinflammatory and promote synapse loss.”
“Genetic findings have highlighted key roles for microglia in the pathology of neurodegenerative conditions such as Alzheimer’s disease (AD),” the researchers wrote. “A number of mutations in the microglial protein triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for developing AD, most notably the R47H/+ substitution. We employed gene editing and stem cell models to gain insight into the effects of the TREM2 R47H/+ mutation on human-induced pluripotent stem cell-derived microglia. We found transcriptional changes affecting numerous cellular processes, with R47H/+ cells exhibiting a proinflammatory gene expression signature.”
?This TREM2 R47H/+ mutation is a pretty important risk factor for Alzheimer?s disease,? said study lead author Jay Penney, PhD, a former postdoc in the MIT lab of Picower professor Li-Huei Tsai. Penney is now an incoming assistant professor at the University of Prince Edward Island. ?This study adds clear evidence that microglia dysfunction contributes to Alzheimer?s disease risk.?
Tsai and Penney?s team shows that human microglia with the R47H/+ mutation in the TREM2 protein exhibit several deficits related to Alzheimer?s pathology.
The study is not the first to ask how the TREM2 R47H/+ mutation contributes to Alzheimer?s, but it may advance scientists? emerging understanding, Penney explained. Early studies suggested that the mutation simply robbed the protein of its function, but the new evidence reveals while microglia do exhibit reduced debris clearance and injury response, they become overactive in other ways, such as their overzealous inflammation and synapse pruning.
?There is a partial loss of function but also a gain of function for certain things,? Penney said.
Penney, Tsai, and their co-authors focused their work on human microglia cell cultures. In some of the stem cells they then used CRISPR gene editing to insert the R47H/+ mutation and then cultured both edited and unedited stem cells to become microglia.
The team then looked to see how harboring the mutation affected each cell lines’ expression of its genes. The scientists measured more than 1,000 differences but an especially noticeable finding was that microglia with the mutation increased their expression of genes associated with inflammation and immune responses. Then, when they exposed microglia in culture to chemicals that simulate infection, the mutant microglia demonstrated a significantly more pronounced response than normal microglia, suggesting that the mutation makes microglia much more inflammation-prone.
As the molecular mechanisms underlying microglial dysfunction become clearer, Penney said, drug developers will gain critical insights into ways to target the higher disease risk associated with the TREM2 R47H/+ mutation.
?Our findings highlight multiple effects of the TREM2 R47H/+ mutation likely to underlie its association with Alzheimer?s disease risk and suggest new nodes that could be exploited for therapeutic intervention,? the authors concluded.
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