Contributed by Hayk Davtyan, Ph.D. and Christel Claes, Ph.D.
While the word “mutation” may conjure up alarming notions, a mutation in brain immune cells serves a positive role in protecting people against Alzheimer’s disease. Now UCI MIND biologists have discovered the mechanisms behind this crucial process. Their paper appears in the journal Alzheimer’s and Dementia.
The investigation centered on a variant of the PLCG2 gene, which makes the instructions for producing an enzyme important to brain immune cells called microglia. “Recently the mutation, which is known as P522R, was shown to lower the risk of developing late-onset Alzheimer’s,” said Hayk Davtyan, Ph.D., senior researcher in the laboratory of Professor Mathew Blurton-Jones, where the study was conducted. The project was led by Christel Claes, Ph.D., the paper’s first author.
The scientists 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 the first evidence to explain how this protective mutation might reduce Alzheimer’s risk,” Davtyan said. The variant also increased the number of T-cells, or white blood immune system cells, in the brain suggesting that it may increase the activation of other important aspects of immune function.
The results will help in designing further studies to understand exactly how microglia and T-cells interact to slow Alzheimer’s progression. “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,” he said. “For us as scientists, it is crucial to find new strategies to treat or prevent this disease that is taking such a toll on humanity.”
The project was supported by a BrightFocus Postdoctoral Fellowship, the Cure Alzheimer’s Fund, National Institutes of Health and National Institute on Aging.