Background: TREM2 is associated with several neurodegenerative diseases. Results: ApoE bound to TREM2 and increased phagocytosis of apoptotic neurons by microglia. Alzheimer disease (AD) risk-associated TREM2-R47H mutant had a reduced binding to apoE. Conclusion: ApoE is a novel ligand for TREM2. Interaction between apoE and TREM2 likely regulates phagocytosis of apoEbound apoptotic neurons. Significance: Interaction between two AD risk-associated proteins modulates microglial function.

Zhong et al. describe two novel roles for soluble TREM2 (sTREM2) in regulation of proinflammatory responses and prevention of cellular apoptosis in microglia.

Triggering Receptor Expressed on Myeloid cells 2 (TREM2), which is expressed on myeloid cells including microglia in the CNS, hasrecently been identified as a risk factor for Alzheimer's disease (AD). TREM2 transmits intracellular signals through its transmembrane binding partner DNAX-activating protein 12 (DAP12). Homozygous mutations inactivating TREM2 or DAP12 lead to Nasu-Hakola disease; however, how AD risk-conferring variants increase AD risk is not clear. To elucidate the signaling pathways underlying reduced TREM2 expression or loss of function in microglia, we respectively knocked down and knocked out the expression of TREM2 in in vitro and in vivo models. We found that TREM2 deficiency reduced the viability and proliferation of primary microglia, reduced microgliosis in Trem2 Ϫ / Ϫ mouse brains, induced cell cycle arrest at the G 1 /S checkpoint, and decreased the stability of ␤-catenin, a key component of the canonical Wnt signaling pathway responsible for maintaining many biological processes, including cell survival. TREM2 stabilized ␤-catenin by inhibiting its degradation via the Akt/GSK3␤ signaling pathway. More importantly, treatment with Wnt3a, LiCl, or TDZD-8, which activates the ␤-catenin-mediated Wnt signaling pathway, rescued microglia survival and microgliosis in Trem2 Ϫ / Ϫ microglia and/or in Trem2 Ϫ / Ϫ mouse brain. Together, our studies demonstrate a critical role of TREM2-mediated Wnt/␤-catenin pathway in microglial viability and suggest that modulating this pathway therapeutically may help to combat the impaired microglial survival and microgliosis associated with AD.

Nuclear factor E2–related factor 2 (Nrf2) is a transcription factor that functions as a master regulator of the cellular adaptive response to oxidative stress. Our previous studies showed that Nrf2 plays a critical role in adipogenesis by regulating expression of CCAAT/enhancer-binding protein β and peroxisome proliferator–activated receptor γ. To determine the role of Nrf2 in the development of obesity and associated metabolic disorders, the incidence of metabolic syndrome was assessed in whole-body or adipocyte-specific Nrf2-knockout mice on a leptin-deficient ob/ob background, a model with an extremely positive energy balance. On the ob/ob background, ablation of Nrf2, globally or specifically in adipocytes, led to reduced white adipose tissue (WAT) mass, but resulted in an even more severe metabolic syndrome with aggravated insulin resistance, hyperglycemia, and hypertriglyceridemia. Compared with wild-type mice, WAT of ob/ob mice expressed substantially higher levels of many genes related to antioxidant response, inflammation, adipogenesis, lipogenesis, glucose uptake, and lipid transport. Absence of Nrf2 in WAT resulted in reduced expression of most of these factors at mRNA or protein levels. Our findings support a novel role for Nrf2 in regulating adipose development and function, by which Nrf2 controls the capacity of WAT expansion and insulin sensitivity and maintains glucose and lipid homeostasis.