3d illustration of the human brain with alzheimer’s disease - dementia
Credit: Lars Neumann/Getty Images

The P522R variant of PLCG2, expressed by microglia, is associated with reduced risk of Alzheimer’s disease (AD). However, the impact of this protective variant on microglial has not been fully understood. Now, researchers at the University of California, Irvine, have demonstrated in mice how this gene variant serves a positive role in protecting people against AD.

Their findings are published in the journal Alzheimer’s and Dementia.

“Recently the mutation, which is known as P522R, was shown to lower the risk of developing late-onset Alzheimer’s,” explained Hayk Davtyan, PhD, senior researcher in the laboratory of Mathew Blurton-Jones, professor of neurobiology & behavior, where the study was conducted. The project was led by assistant project scientist Christel Claes, PhD, the paper’s first author.

The researchers used CRISPR gene-editing technology to generate the protective mutation in human stem cells and then implanted microglia derived from those stem cells into humanized rodent models of Alzheimer’s disease.

“Our research showed for the first time that the P522R variant increased expression levels of several microglial genes that are reduced in people with Alzheimer’s. This provides some of the first evidence to explain how this protective mutation might reduce Alzheimer’s risk,” Davtyan noted.

The researchers also observed the variant increased the number of T cells in the brain.

“Beyond that, the next step could be to identify drugs that can safely increase the activity of the PLCG2 enzyme and further promote protective microglial functions. It is well known that the PLCG2 P522R mutation increases TREM2 downstream signaling, an AD risk variant, thus it will be very interesting to study the effect of TREM2 stimulating antibodies on microglia-T cell crosstalk. Studies like ours pave the way to find new strategies to treat or prevent this disease that is taking such a toll on humanity, this is what drives us as neuroscientists,” said Davtyan.

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