Abstract Body

The APOE gene is the strongest genetic risk factor for Alzheimer’s disease (AD) with APOE4 strongly increases the risk by driving amyloid pathology, although several amyloid-β (Aβ)-independent pathways such as impaired lipid metabolism and compromised cerebrovascular function also contribute. Studies from our group and others have identified apoE, phospholipids, and Aβ as ligands for TREM2, a microglia-specific gene in the brain with its variants also strongly linked to AD risk. To further address the molecular mechanisms underlying apoE- and TREM2-related AD risk, we generated conditional mouse models expressing human APOE3 or APOE4 specifically in microglia in the murine Apoe knockout background. Similar mouse models were also generated for the common allele TREM2 or AD-risk associated TREM2-R47H. In the absence of amyloid pathology, we observed enhanced synaptic functions and behaviors, as well as microglial responses to acute injury, by apoE3 and TREM2, but not apoE4 or TREM2-R47H. In the presence of amyloid pathology, both apoE4 and TREM2-R47H exhibited loss-of-function effects in microglial clustering around the amyloid plaques associated with reduced amyloid pathology compared with apoE3 or TREM2, respectively. Molecular profiling by single cell RNA-sequencing revealed apoE isoform- or TREM2-specific pathways underlying differential microglial functions and their responses to amyloid pathology. Interestingly, we found that apoE expression is highly modulated by TREM2, suggesting that apoE is functionally downstream of TREM2. Together, our studies define critical roles of apoE and TREM2 in microglial functions, establishing a common neuroimmune pathway modulated by the two strong genetic risk factors for AD.