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Erythropoietin signaling in peripheral macrophages is required for systemic β-amyloid clearance
The EMBO Journal ( IF 11.4 ) Pub Date : 2022-10-10 , DOI: 10.15252/embj.2022111038
Lu Xu 1, 2, 3 , Lei Li 1 , Cai-Long Pan 1, 2 , Jing-Jing Song 1 , Chen-Yang Zhang 1 , Xiang-Hui Wu 1 , Fan Hu 4 , Xue Liu 1 , Zhiren Zhang 5 , Zhi-Yuan Zhang 1, 2, 3, 6
Affiliation  

Impaired clearance of beta-amyloid (Aβ) is a primary cause of sporadic Alzheimer's disease (AD). Aβ clearance in the periphery contributes to reducing brain Aβ levels and preventing Alzheimer's disease pathogenesis. We show here that erythropoietin (EPO) increases phagocytic activity, levels of Aβ-degrading enzymes, and Aβ clearance in peripheral macrophages via PPARγ. Erythropoietin is also shown to suppress Aβ-induced inflammatory responses. Deletion of EPO receptor in peripheral macrophages leads to increased peripheral and brain Aβ levels and exacerbates Alzheimer's-associated brain pathologies and behavioral deficits in AD-model mice. Moreover, erythropoietin signaling is impaired in peripheral macrophages of old AD-model mice. Exogenous erythropoietin normalizes impaired EPO signaling and dysregulated functions of peripheral macrophages in old AD-model mice, promotes systemic Aβ clearance, and alleviates disease progression. Erythropoietin treatment may represent a potential therapeutic approach for Alzheimer's disease.

中文翻译:

外周巨噬细胞中的促红细胞生成素信号传导是全身性β-淀粉样蛋白清除所必需的

β-淀粉样蛋白 (Aβ) 清除受损是散发性阿尔茨海默病 (AD) 的主要原因。外周 Aβ 清除有助于降低大脑 Aβ 水平并预防阿尔茨海默病的发病机制。我们在此表明​​,促红细胞生成素 (EPO) 通过 PPARγ 增加外周巨噬细胞的吞噬活性、Aβ 降解酶水平和 Aβ 清除率。促红细胞生成素还被证明可以抑制 Aβ 诱导的炎症反应。外周巨噬细胞中 EPO 受体的缺失会导致外周和大脑 Aβ 水平升高,并加剧 AD 模型小鼠中与阿尔茨海默病相关的大脑病理和行为缺陷。此外,老年 AD 模型小鼠的外周巨噬细胞中促红细胞生成素信号传导受损。外源性促红细胞生成素可使老年 AD 模型小鼠中受损的 EPO 信号传导和外周巨噬细胞功能失调正常化,促进全身 Aβ 清除,并减轻疾病进展。促红细胞生成素治疗可能代表阿尔茨海默病的潜在治疗方法。
更新日期:2022-10-10
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