TREM2 in Alzheimer's Disease and Related Dementias

Mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) have been identified as risk factors for late-onset AD. In the central nervous system, TREM2 is expressed primarily in microglia, and shown to play important roles in modulating multiple microglial functions including survival, phagocytosis and inflammatory responses.

Importantly, two prominent AD risk genes, TREM2 and APOE, play critical roles in triggering, sustaining or controlling the acquisition of the disease-associated phenotypes of microglia. This discovery raises the possibility that targeting TREM2 or APOE pathways in microglia could be a potential disease-modifying therapy for AD.

The Zhao lab is working to understand the dynamic effects of TREM2 and its risk variants, such as R47H and H157Y, on microglial functions and immune-related pathways during the neurodegenerative process. Toward this end, the lab's team uses tools that include postmortem human brain tissue, iPSC-derived cellular and organoid models, and transgenic animal models.

Research highlights

• Zhao N, Qiao W, Li F, Ren Y, Zheng J, Martens YA, Wang X, Li L, Liu CC, Chen K, Zhu Y, Ikezu TC, Li Z, Meneses AD, Jin Y, Knight JA, Chen Y, Bastea L, Linares C, Sonustun B, Job L, Smith ML, Xie M, Liu YU, Umpierre AD, Haruwaka K, Quicksall ZS, Storz P, Asmann YW, Wu LJ, Bu G. Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia. Journal of Experimental Medicine. 2022; doi:10.1084/jem.20212479.
• Qiao W, Chen Y, Martens YA, Liu CC, Knight JA, Li F, Chen K, Kurti A, Shue F, Dacquel M, Fryer JD, Zhao N, and Bu G. TREM2-H157Y increases soluble TREM2 production and reduces amyloid pathology. bioRxiv. 2021; doi:10.1101/2021.10.04.463020.