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MS4A4A is the major regulator of TREM2 levels

Drs. Harari, Benitez, Karch and Cruchaga leveraged biospecimens obtained from large and well-characterized human cohorts to identify a novel protective gene for Alzheimer disease, MS4A4A, that is also the major regulator of TREM2.

This study provides a strong evidence of a biological link between TREM2 and MS4A4A in microglia in the context of AD. However, we know that TREM2 is an important molecule in microglia and TREM2/MS4A4A pathways could potentially modulate microglia functions in other neurological/neurodegenerative diseases. Therefore, our study opens a new direction of research not only in the AD field, but with a much broader view for a better understanding of microglia biology in the context of several neurological disorders.

Before this study, it was known that rare variants in TREM2 increase AD risk, but it was not clear if TREM2 was involved in disease of those individuals without the rare TREM2 variants. In addition, we knew that TREM2 goes to the membrane where it is cleaved, but It was not clear if higher or lower levels of TREM2 were good or bad in relation to AD. Previous studies reported that MS4A4A is associated with AD risk. However, the function and mechanism of MS4A4A was unknown. In this study, we reported for the first time that MS4A4A is the major regulator of TREM2 levels. This is important, because we are now able to explain the reason why MS4A4A is associated with AD, which is by regulating TREM2. One of the most important findings of this study is that TREM2 is involved in AD in general, and that higher TREM2 levels are protective. These findings open the door to new therapeutic strategies.

This study was published on Science Translational Medicine.
This finding was covered by the Washington University NewsHub
and several news media, including MedIndia, Technology Networks, Science Daily, MedPage Today or Medical Xpress

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