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Meningeal macrophages alleviate social memory defects in an early Alzheimer's disease model
Shixin Ding1,2, Sijia Chen1,2, Yuxi Jin1,2
1Jiangsu Key Laboratory of Neurodegeneration, Nanjing Medical University, Nanjing, 211166, China.
Abstract:
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.
Insights
Meningeal macrophages, particularly those producing TGF-β1, protect against early Alzheimer's disease (AD) pathology by clearing amyloid-beta and supporting myelin. Targeting these macrophages offers a potential therapeutic strategy for neurodegenerative diseases.
Area of Science:
- Neuroimmunology
- Neurodegenerative Diseases
- Cellular Biology
Background:
- Macrophages are abundant in the meninges, but their specific roles in brain health and disease are not fully understood.
- Alzheimer's disease (AD) pathogenesis involves complex interactions between immune cells and pathological hallmarks like amyloid-beta.
- The function of meningeal macrophages in early AD-like pathology requires further elucidation.
Purpose of the Study:
- To investigate the role of meningeal macrophages in the pathogenesis of Alzheimer's disease (AD).
- To explore the impact of transforming growth factor-β1 (TGF-β1) produced by meningeal macrophages on AD pathology.
- To assess the therapeutic potential of modulating meningeal macrophage activity in early AD.
Main Methods:
- Analysis of cerebrospinal fluid from patients with mild cognitive impairment and meninges from young 5×FAD mice.
- Experimental manipulation of meningeal macrophages, including inhibition of TGF-β1 and supplementation with M2-like macrophages.
- Assessment of social behavior, amyloid-beta accumulation, myelin integrity, oligodendrocyte maturation, and microglial phagocytosis in the medial prefrontal cortex (mPFC).
Main Results:
- Increased M2-like macrophages with high TGF-β1 levels were observed in early AD indicators.
- Inhibition of TGF-β1 in meningeal macrophages worsened AD-like symptoms and pathology in 5×FAD mice.
- Supplementation with M2-like macrophages or enhanced TGF-β1 expression ameliorated these pathological effects.
- Meningeal macrophages were found to clear amyloid-beta and promote oligodendrocyte maturation and microglial phagocytosis via TGF-β1.
Conclusions:
- Meningeal macrophages play a protective role against early Alzheimer's disease-like pathology.
- TGF-β1 secreted by meningeal macrophages is crucial for myelin maintenance and immune cell function in the context of AD.
- Modulating meningeal macrophage activity represents a promising therapeutic avenue for neurodegenerative diseases.
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