Uncoupling of synaptic loss from amyloid burden by an Alzheimer's disease protective variant of PLCγ2.

Ryan J. Bevan; Emily Maguire; Tom J. Phillips; Elena Simonazzi; Marieta Vassileva; Julie H. Williams; Philip R. Taylor

doi:10.1101/2023.09.22.558987

NeurosciencebioRxivSep 22, 2023

Preprint

Uncoupling of synaptic loss from amyloid burden by an Alzheimer's disease protective variant of PLCγ2.

Ryan J. Bevan iD, Emily Maguire iD, Tom J. Phillips iD, Elena Simonazzi iD, Marieta Vassileva iD, Julie H. Williams iD, Philip R. Taylor iD

Abstract

A rare coding missense variant (rs72824905; P522R) in PLCG2 decreases the risk of late-onset Alzheimers disease, but how this protective effect is mediated is unclear. Here we demonstrate a mechanism for this protection, the R522 variant of PLC{gamma}2 alters microglial activity leading to a marked preservation of synaptic integrity and reduced peri-plaque microglial engulfment of synapses independently of amyloid burden. Our data advocate for a direct central role of PLC{gamma}2 in mediating synaptic loss as part of the pathological process of Alzheimers disease (AD), prioritising it as a therapeutic target and modulator of disease.

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