1986-P: Hippocampal Overexpression of Triggering Receptor Expressed on Myeloid Cell 2 (TREM2) Ameliorates High-Fat Diet-Induced Neurocognitive Impairment via Modulating Microglial M1/M2 Polarization

Abstract

Objective: Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) share several common pathophysiological features. It was reported that rare variant of triggering receptor expressed on myeloid cell 2 (TREM2) increases risk of developing AD, suggesting the involvement of TREM2 and microglia in AD development. It is still unknown whether TREM2 is related to neurocognitive impairment of T2DM. Methods: Male C57BL/6J mice were maintained high fat diet (HFD). TREM2 was overexpressed in hippocampus of mice 40 weeks after HFD feeding, using an adeno-associated virus vector (AAV)-mediated gene delivery. Morris water maze, Y maze-spontaneous alteration test, novel object recognition test, and open field test were performed 32-36 weeks and 48-50 weeks after HFD feeding. Mouse microglial BV-2 cells were used to examine microglial polarization after TREM2 overexpression or knockdown. Results: HFD feeding caused rapid weight gain, glucose intolerance and significant impairment in learning and memory as well as anxiety-related behaviors. Compared with empty AAV delivery, TREM2 AAV significantly ameliorated glucose homeostasis and neurocognitive impairment without altering body weight in HFD mice. Hippocampal delivery of TREM2 upregulated synaptic protein spinophilin and PSD95, suggesting improvement in synaptic transmission. Microglial M2 polarization markers, such as Arg-1, YM1/2, CD206 and anti-inflammatory cytokines, were positively correlated to TREM2 levels either in the hippocampus of HFD mice or BV-2 cells in vitro. Conclusion: Hippocampal TREM2 plays an important role in improving obesity-induced cognitive dysfunction and anxiety-like behavior via modulating microglial polarization toward M2 anti-inflammatory subtype. Our study also suggests that TREM2 might be a novel molecular target for the intervention of obesity-associated cognitive decline. Disclosure M. Wu: None. X. Xiao: None. Funding National Natural Science Foundation of China