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bioRxiv · 10.1101/2023.09.22.558987

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

Bevan, R.·Maguire, E.·Phillips, T.·Simonazzi, E.·Vassileva, M.·Williams, J.·Taylor, P.
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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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Bevan, R., Maguire, E., Phillips, T., Simonazzi, E., Vassileva, M., Williams, J., Taylor, P.. 2023-09-22. Uncoupling of synaptic loss from amyloid burden by an Alzheimer's disease protective variant of PLCγ2.. https://doi.org/10.1101/2023.09.22.558987

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