12-LB: Reduced Disease-Associated Microglial Phenotype Is Associated with Diabetes-Associated Alzheimer’s Disease

Abstract

Introduction: Type 2 diabetes mellitus (T2DM) has a significantly increased risk of developing Alzheimer’s disease (AD). Amyloid-β (Aβ) as one of the main pathological features in AD increases in the brain of T2DM. A recent study identified a protective novel subset of microglial­ in AD—disease-associated microglia (DAM), the activation of which depends on TREM2(a myeloid cell membrane receptor) to phagocytose Aβ plaques. However, as to how T2DM increases Aβ deposition and the relationship between T2DM with DAM remain elusive. Objective: This study aims to explore the relationship between progression of T2DM with DAM and Aβ. Methods: In vivo experiment, the deposition of Aβ, inflammation as well as the phenotype of DAM were evaluated by RT-PCR and immunofluorescence in the cortex and hippocampus of 10-,15-,20-week old db/db mice and the age-matched WT control. Additionally, the effects of high insulin-induced insulin resistance (100nM) on the DAM signature markers and the production of inflammatory cytokines in BV-2 microglial cells were investigated in vitro. Results: We found the soluble and insoluble Aβ40, Aβ42, Aβ plaques as well as inflammation in the cortex and hippocampus increased in the progression of T2DM. Correspondingly, the DAM phenotype was reduced in the cortex and hippocampus at relatively early stage of T2DM (10 weeks and 15 weeks), while it increased reactively at the late stage (20 weeks). Likewise, high insulin-stimulated BV-2 microglial cells showed reduced Trem2 level and DAM signature markers and increase inflammation as well as Erk1/2 level. However, after the treatment of Erk1/2 inhibitor, the BV-2 cells under high insulin showed restored Trem2 level and DAM phenotype. Conclusion: T2DM brain has decreased DAM phenotype at a relatively early stage, which may explain the increased Aβ deposition. This may involve Erk1/2 -Trem2 signaling pathway, which could be a potential candidate especially at early stages for preventing T2DM-induced AD. Disclosure X. Peng: None. Funding National Natural Science Foundation of China (81974114)