Alzheimer's disease (AD) pathology is characterized by amyloid-β (Aβ) deposition and tau hyper-phosphorylation, accompanied by a progressive cognitive decline. Monocytes have been recently shown to play a major role in modulating Aβ pathology, and thereby have been pointed as potential therapeutic targets. However, the main challenge remains in identifying clinically relevant interventions that could modulate monocyte immune functions in absence of undesired off-target effects. Erythropoietin (EPO), a key regulator of erythrocyte production, has been shown to possess immunomodulatory potential and to provide beneficial effects in preclinical models of AD. However, the transition to use recombinant human EPO in clinical trials was hindered by unwanted erythropoietic effects that could lead to thrombosis. Here, we used a recently identified non-erythropoietic analogue of EPO, ARA 290, to evaluate its therapeutic potential in AD therapy. We first evaluated the effects of early systemic ARA 290 administration on AD-like pathology in an early-onset model, represented by young APP/PS1 mice. Our findings indicate that ARA 290 early treatment decelerated Aβ pathology progression in APP/PS1 mice while improving cognitive functions. ARA 290 potently increased the levels of total monocytes by specifically stimulating the generation of Ly6C^Low patrolling subset, which are implicated in clearing Aβ from the cerebral vasculature, and subsequently reducing overall Aβ burden in the brain. Moreover, ARA 290 increased the levels of monocyte progenitors in the bone marrow. Using chimeric APP/PS1 mice in which Ly6C^Low patrolling subset are selectively depleted, ARA 290 was inefficient in attenuating Aβ pathology and ameliorating cognitive functions in young animals. Interestingly, ARA 290 effects were compromised when delivered in a late-onset model, represented by aged APP1/PS1. In aged APP/PS1 mice in which AD-like pathology is at advanced stages, ARA 290 failed to reverse Aβ pathology and to increase the levels of circulating monocytes. Our study suggests that ARA 290 early systemic treatment could prevent AD-like progression via modulation of monocyte functions by specifically increasing the ratio of patrolling monocytes.

阿尔茨海默病 (AD) 病理学的特征是淀粉样蛋白-β (Aβ) 沉积和 tau 过度磷酸化，并伴有进行性认知衰退。最近已显示单核细胞在调节 Aβ 病理学中起主要作用，因此已被指出为潜在的治疗靶点。然而，主要挑战仍然是确定临床相关干预措施，这些干预措施可以在没有不希望的脱靶效应的情况下调节单核细胞免疫功能。促红细胞生成素 (EPO) 是红细胞生成的关键调节剂，已被证明具有免疫调节潜力并在 AD 的临床前模型中提供有益效果。然而，在临床试验中向使用重组人 EPO 的过渡受到可能导致血栓形成的有害红细胞生成作用的阻碍。这里，我们使用最近发现的 EPO 的非红细胞生成类似物 ARA 290 来评估其在 AD 治疗中的治疗潜力。我们首先在以年轻 APP/PS1 小鼠为代表的早发模型中评估了早期全身 ARA 290 给药对 AD 样病理的影响。我们的研究结果表明，ARA 290 早期治疗减缓了 APP/PS1 小鼠的 Aβ 病理进展，同时改善了认知功能。ARA 290 通过特异性刺激 Ly6C 的生成，有效提高总单核细胞的水平 我们的研究结果表明，ARA 290 早期治疗减缓了 APP/PS1 小鼠的 Aβ 病理进展，同时改善了认知功能。ARA 290 通过特异性刺激 Ly6C 的生成，有效提高总单核细胞的水平 我们的研究结果表明，ARA 290 早期治疗减缓了 APP/PS1 小鼠的 Aβ 病理进展，同时改善了认知功能。ARA 290 通过特异性刺激 Ly6C 的生成，有效提高总单核细胞的水平^低巡逻亚群，涉及从脑血管系统中清除 Aβ，并随后减少大脑中的整体 Aβ 负担。此外，ARA 290 增加了骨髓中单核细胞祖细胞的水平。使用 Ly6C^{低的嵌合 APP/PS1 小鼠}巡逻子集被选择性地耗尽，ARA 290 在减弱 Aβ 病理学和改善年轻动物的认知功能方面效率低下。有趣的是，ARA 290 效果在以老化的 APP1/PS1 为代表的晚发模型中受到影响。在 AD 样病理处于晚期的老年 APP/PS1 小鼠中，ARA 290 未能逆转 Aβ 病理并增加循环单核细胞的水平。我们的研究表明，ARA 290 早期全身治疗可以通过特异性增加巡逻单核细胞的比例来调节单核细胞功能来预防 AD 样进展。