Soluble TGF-β decoy receptor TGFBR3 exacerbates AD lesions by modifying microglial function

Abstract

Abstract Alzheimer’s disease (AD) is one of the major causative factors that induces progressive dementia, which is characterized by memory loss and progressive neurocognitive dysfunction. To elucidate the molecular mechanism contributing to AD, we analyzed an RNA-seq cohort of temporal cortex in AD patients using a bioinformatics workflow and demonstrated that transforming growth factor beta receptor 3 is a crucial gene regulating AD. Nevertheless, soluble TGFBR3 (sTGFBR3) rather than membrane-bound TGFBR3 is abnormally elevated in AD patients and animals. We then demonstrated that sTGFBR3 knockdown restored spatial learning and memory deficits in APP/PS1 and STZ-induced tau hyperphosphorylation mice. Mechanistically, sTGFBR3 knockdown promoted microglial polarization to the M2 phenotype from the M1 phenotype, inhibited proinflammatory and chemotactic activity, and enhanced phagocytic activity. In addition, sTGFBR3 knockdown significantly reduced acute LPS-induced neuroinflammation and ameliorated STZ-induced neuronal function impairment. These findings suggest that sTGFBR3 is a potential therapeutic target for AD.