The Chemokine-like Receptor 1 Deficiency Improves Cognitive Deficits of AD Mice and Attenuates Tau Hyperphosphorylation via Regulating Tau Seeding
Haibo Zhang, Aihua Lin, Ping Gong, Yanqing Chen, Richard D. Ye, Feng Qian, Yan Zhang, Yang Yu
Abstract
Pathologic features of Alzheimer9s 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 <i>in vivo</i> and in the neuronal cells <i>in vitro</i>. 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. <b>SIGNIFICANCE STATEMENT</b> 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 <i>in vivo</i> and in neuronal cells <i>in vitro</i>. 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.