Simonazzi, E. | Search bioRxiv

bioRxiv2023

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

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.

neuroscience↗

bioRxiv2021

Abi3 regulates microglial ramification and dynamic tissue surveillance in vivo.

A rare coding variant of Abelson-interactor gene family member 3 (Abi3) is associated with increased risk of late-onset Alzheimers Disease (AD). Although Abi3 is recognised as a core microglial gene, its role in microglia is largely unknown. Here we demonstrate that Abi3 is crucial for normal microglial morphology, distribution, and homeostatic tissue surveillance activity in vivo.

neuroscience↗