FH-like protein 1-Y402H mutation promoted microglial synapse phagocytosis and cognitive impairment in Alzheimer's disease model

Abstract

Abstract Background Studies demonstrated that the complement system was involved in the pathogenesis of Alzheimer’s disease (AD). A genetic screening study in a Chinese cohort identified that two single nucleotide polymorphisms (SNPs) of the complement regulator Factor H (CFH) rs1061170 (Y402H) and rs800292 (V62I) were robustly associated with AD. FH-like protein 1 (FHL-1) is a short alternative splicing derived from CFH gene. Due to its smaller size and more diffuseness, FHL-1 may provide greater protection via blocking complement 3 (C3). This study aims to investigate the role of FHL-1 and its two mutants V62I and Y402H via lentiviral overexpression of FHL-1 wild type (FHL-1WT), FHL-1V62I, and FHL-1Y402H in 5×FAD mice. Methods We produced lentivirus of control, FHL-1 wild type (FHL-1WT), FHL-1V62I, and FHL-1Y402H and injected into the hippocampus 5×FAD mice. We employed immunostaining and behavior test to investigate the role of these vectors in AD model. Results The result showed that overexpression of FHL-1WT and FHL-1V62I but not FHL-1Y402H ameliorated cognitive impairment in 5×FAD mice. In the other hand, overexpression of FHL-1WT, FHL-1V62I, and FHL-1Y402H did not differently affected the plaque load and astrocytic status. The V62I mutation lightly increased the diffuseness index of amyloid plaque and reduced the number of plaque-associated microglia. Notably, overexpression of FHL-1Y402H prominently promoted synapse phagocytosis by microglia in 5×FAD mice compared to FHL-1WT and FHL-1V62I. Conclusions this indicated that microglia-mediated synapse phagocytosis via complement system may be a key contributor to the cognitive impairment in 5×FAD mice independent on amyloid plaque. Our study provides a clue that blocking microglia-mediated synapse phagocytosis would be an effective therapeutic approach and strategy for AD.