Pathologic features of Alzheimer's disease (AD) include accumulation of amyloid β (Aβ) and hyperphosphorylated tau protein. We have shown previously that the chemokine-like receptor 1 (CMKLR1) is a functional receptor for Aβ, and CMKLR1 contributes to the uptake of Aβ. However, it is unclear whether CMKLR1 ameliorates or aggravates the process of AD. Here, we show that deletion of the gene coding for CMKLR1 significantly increased Aβ deposits in brains of both male and female amyloid β precursor protein/presenilin-1 mice. However, it markedly decreased the mortality of these mice. Behavioral studies found that CMKLR1 deficiency improved cognitive impairment of male and female amyloid β precursor protein/presenilin-1 mice and intracerebroventricular-streptozotocin injection AD mice. We further explored the effect of CMKLR1 on tau pathology. We found that CMKLR1 deficiency or inhibition attenuated the hyperphosphorylation of tau in brains of AD mice in vivo and in the neuronal cells in vitro. The expression of CMKLR1 on the neurons affected tau phosphorylation by participating in tau seeding. Together, these results uncover a novel mechanism of CMKLR1 in the pathologic process of AD and suggest that inhibiting the promotion effect of CMKLR1 on tau seeding may provide a new strategy for the treatment of AD.

SIGNIFICANCE STATEMENT Evidence suggests that inflammation is involved in the pathologic progression of AD. The chemokine-like receptor 1 (CMKLR1), belonging to the family of GPCRs, is able to bind and uptake amyloid β. We show here, for the first time, that, although CMKLR1 deficiency increased amyloid β deposits in AD mice, it reduced the mortality and improved the cognitive deficits of AD mice. We furthermore show that CMKLR1 deficiency or inhibition attenuated tau hyperphosphorylation in brains of AD model mice in vivo and in neuronal cells in vitro. Finally, we first discovered that the expression of CMKLR1 on neurons affected tau phosphorylation by participating in tau seeding. These findings suggest that inhibition of CMKLR1 may provide a new strategy for the treatment of AD.

阿尔茨海默氏病（AD）的病理特征包括淀粉样蛋白β（Aβ）和磷酸化tau蛋白的积累。先前我们已经证明趋化因子样受体1（CMKLR1）是Aβ的功能性受体，而CMKLR1有助于Aβ的摄取。但是，尚不清楚CMKLR1是改善还是加重AD的过程。在这里，我们显示删除编码CMKLR1的基因会明显增加雄性和雌性淀粉样β前体蛋白/早老素1小鼠的大脑中的Aβ沉积。但是，它明显降低了这些小鼠的死亡率。行为研究发现，CMKLR1缺乏症改善了雌性和雌性β-淀粉样蛋白前体蛋白/ presenilin-1小鼠和脑室内链脲佐菌素注射AD小鼠的认知障碍。我们进一步探讨了CMKLR1对tau病理的影响。在体内和在神经细胞体外。CMKLR1在神经元上的表达通过参与tau接种影响tau磷酸化。总之，这些结果揭示了CMKLR1在AD的病理过程中的新机制，并表明抑制CMKLR1对tau种子的促进作用可能为AD的治疗提供新的策略。

意义声明证据表明炎症与AD的病理进展有关。属于GPCR家族的趋化因子样受体1（CMKLR1）能够结合并摄取淀粉样蛋白β。我们首次在这里表明，尽管CMKLR1缺乏症增加了AD小鼠的淀粉样β沉积物，但它降低了AD小鼠的死亡率并改善了其认知缺陷。我们进一步表明，CMKLR1缺乏或抑制可减弱AD模型小鼠体内和体外神经元细胞中的tau过度磷酸化。。最后，我们首先发现CMKLR1在神经元上的表达通过参与tau接种影响tau磷酸化。这些发现表明，抑制CMKLR1可能为AD的治疗提供新的策略。