APOE4/4 is associated with reduced mGlu3R in the amyloid plaque microenvironment in Alzheimer’s disease

AD involves β-amyloid (Aβ) accumulation and impaired clearance. Astrocytes contribute to Aβ removal via mGlu3R. Our laboratory previously showed that mGlu3R activation promotes non-amyloidogenic APP processing and increases astrocytic Aβ uptake. We asked whether mGlu3R is associated with APOE4-related risk. Human brain transcriptomic data from AD patients and controls were stratified by APOE3/3, APOE3/4 and APOE4/4, and GRM3 expression was analyzed in plaque, near-plaque and far-plaque. APOE4/4 showed reduced GRM3 vs controls (pADJ=2.58×10⁻²), driven by the plaque region (pADJ=2.20×10⁻²). No significant differences were found in other regions or in APOE3/3 and APOE3/4. We next investigated the ApoE–mGlu3R relationship. In primary rat astrocytes, LY379268 increased ApoE expression by 25%, although this was not significant. In PDAPP-J20 mice, previously shown by our laboratory to have reduced hippocampal mGlu3R, ApoE mRNA was significantly reduced in hippocampus vs NTg controls (p=0.049), but not in cortex. In primary mouse astrocytes, 30μM NAAG did not alter ApoE or LRP1 mRNA levels. Finally, Aβ uptake was assessed across an NAAG dose-response curve; analysis is ongoing. Together, these findings identify a specific association between APOE4/4 and reduced GRM3 at amyloid plaques. Reduced hippocampal ApoE in J20 mice, together with the role of mGlu3R in astrocytic Aβ clearance, supports a potential link between APOE4-related vulnerability and mGlu3R-dependent glial responses.