Meningeal macrophages alleviate social memory defects in an early Alzheimer's disease model.

Macrophages are enriched in the meninges, but their pathophysiological functions remain unclear. Here, we report the involvement of meningeal macrophages in the pathogenesis of Alzheimer's disease (AD). Specifically, M2-like macrophages with high levels of transforming growth factor-β1 (TGF-β1) were increased in the cerebrospinal fluid of patients with mild cognitive impairment and the meninges of young 5×FAD mice. Targeting meningeal macrophages to inhibit TGF-β1 exacerbated social behavioral defects, β-amyloid (Aβ) accumulation, and myelin damage in the medial prefrontal cortex (mPFC) of 5×FAD mice. Conversely, supplementation with M2-like macrophages or viral overexpression of TGF-β1 in meningeal macrophages ameliorated these effects. Mechanistically, meningeal macrophages facilitated the clearance of Aβ and secrete TGF-β1 to enhance oligodendrocyte maturation and microglial phagocytosis in the mPFC, thereby promoting myelin-dependent social memory. Collectively, the results of this study reveal that meningeal macrophages counteract early AD-like pathology and serve as a potential therapeutic target for treating neurodegenerative diseases.