| First Author | Zhang H | Year | 2020 |
| Journal | J Neurosci | Volume | 40 |
| Issue | 36 | Pages | 6991-7007 |
| PubMed ID | 32801154 | Mgi Jnum | J:295954 |
| Mgi Id | MGI:6454437 | Doi | 10.1523/JNEUROSCI.0455-20.2020 |
| Citation | Zhang H, et al. (2020) The Chemokine-like Receptor 1 Deficiency Improves Cognitive Deficits of AD Mice and Attenuates Tau Hyperphosphorylation via Regulating Tau Seeding. J Neurosci 40(36):6991-7007 |
| abstractText | Pathologic features of Alzheimer's disease (AD) include accumulation of amyloid beta (Abeta) and hyperphosphorylated tau protein. We have shown previously that the chemokine-like receptor 1 (CMKLR1) is a functional receptor for Abeta, and CMKLR1 contributes to the uptake of Abeta. 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 Abeta deposits in brains of both male and female amyloid beta 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 beta 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 beta. We show here, for the first time, that, although CMKLR1 deficiency increased amyloid beta 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. |
