Alzheimer's Protection by <scp>PLCγ2</scp> Compacts Plaques, Redistributes Microglia, and Protects Synapses in <scp> <i>App</i> ^<i>NL</i> </scp> ^{<i>‐G‐F</i>} Mice

ABSTRACT The Alzheimer's disease protective P522R PLCG2 coding variant (rs72824905) is downstream of TREM2, but how it confers disease protection is poorly understood. Using a Plcg2 ‐R522 knock‐in mouse and Plcg2 ‐P522 control on both wildtype and Alzheimer's disease‐like App NL‐G‐F amyloidosis mouse backgrounds, aged mice were assayed for amyloid load, microglial activity, and synaptic integrity. In the absence of Alzheimer's disease‐like pathology, the R522 variant increased microglial coverage and was associated with reduced ramification complexity, fewer terminal points, and elevated lysosomal CD68 expression. On the App NL‐G‐F background, total amyloid burden was unaffected, but expression of the R522 variant led to increased plaque compaction compared to the P522 common variant. The protective R522 variant was also associated with: enhanced microglial engagement with less compact amyloid plaques; reduced microglial localisation around highly compacted plaques; protection from amyloid‐induced synapse loss; and decreased engulfment of synaptic material by microglia. Our data indicate a significant direct PLCγ2 role in controlling microglial‐plaque interactions and synaptic protection downstream of amyloid deposition, prioritizing it as a therapeutic target, potentially as an adjunct to other approaches, such as those targeting amyloid.