Erythropoietin signaling in peripheral macrophages is required for systemic beta-amyloid clearance

Impaired clearance of beta-amyloid (A beta) is a primary cause of sporadic Alzheimer's disease (AD). A beta clearance in the periphery contributes to reducing brain A beta levels and preventing Alzheimer's disease pathogenesis. We show here that erythropoietin (EPO) increases phagocytic activity, levels of A beta-degrading enzymes, and A beta clearance in peripheral macrophages via PPAR gamma. Erythropoietin is also shown to suppress A beta-induced inflammatory responses. Deletion of EPO receptor in peripheral macrophages leads to increased peripheral and brain A beta 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 A beta clearance, and alleviates disease progression. Erythropoietin treatment may represent a potential therapeutic approach for Alzheimer's disease.