The Role Of Chemokine Like Receptor 1 In Alzheimer’s Disease

Background:Alzheimer’s disease（AD）is a neurodegenerative disease with two major pathological features,senile plaques formed by beta-amyloid protein deposition and neurofibrillary tangles formed by abnormal hyperphosphorylation of tau.Chemokine like receptor 1（CMKLR1）is a G-protein-coupled receptor,commonly found in mononuclear immune cells and adipocytes.CMKLR1 has been reported to be involved in adipogenesis and lung diseases.CMKLR1 is also expressed in the brain,but its function in the nervous system is rarely reported.Our previous study has found that CMKLR1 is a functional receptor of Aβ.Here,we further explore the role of CMKLR1 in AD and its mechanism.Methods:Two AD mouse models were used,the APP/PS1 transgenic AD model and ICV-STZ AD model.Cmklr1 knockout mice(Cmklr1^-/-)were mated with APP/PS1 transgenic mice(APP/PS1^+/-)to obtain APP/PS1 transgenic Cmklr1knockout mice(APP/PS1^+/--Cmklr1^-/-).Cmklr1^-/-mice were also used to establish ICV-STZ AD mice.Morris water maze was used to detect the ability of learning and memory of the mice,open field test was used to detect anxiety degree,elevated plus maze test was used to detect space exploration ability,and rotarod test was used to detect motion balance ability.The phosphorylation of tau protein in the brain and SH-SY5Y cells was examined by western blotting（WB）.The expression of insoluble Aβ,APP,CMKLR1,and MAP2,and activation of glial cells were detected by immunofluorescence（IF）.ICV-TAU mouse model was established to verify the effect of CMKLR1 in tau seeding.Results:CMKLR1 deficiency significantly increased the survival rate of APP/PS1^+/-mice.CMKLR1 deficiency improved the cognitive ability of the above two AD model mice,but had no effect on the anxiety of mice.CMKLR1 deficiency significantly increased the numbers of Aβplaques in the cortex and hippocampus of APP/PS1^+/-mice,increased the soluble Aβ_1-40and Aβ_1-42and promoted the activation of astrocytes in the brain of APP/PS1^+/-mice.Compared with APP/PS1^+/-group,the activation of microglia in the hippocampus was decreased in APP/PS1^+/--Cmklr1^-/-mice group,while the activation of microglia in the cortical wasincreased.In addition,CMKLR1 deficiency alleviated the abnormal hyperphosphorylation of tau in the brains of the two AD model mice.Inhibition of CMKLR1 attenuated hyperphosphorylation of tau protein induced by high glucose treatment in SH-SY5Y cells.CMKLR1 deficiency inhibited hyperphosphorylation of tau protein in hippocampus and cortex of ICV-TAU mice.Conclusion:These results indicate that CMKLR1 deletion can ameliorate cognitive impairment in AD.CMKLR1 may affect the deposition of insoluble Aβby regulating the content of soluble Aβand the activation of glial cells.CMKLR1mediates the phosphorylation level of tau protein and the transmission of phosphorylate tau by tau seeding.Therefore,the regulation of CMKLR1 may contribute to the prevention and treatment of AD.