CHIT1 Influences The Pathogenesis And Function Of Alzheimer’s Disease By Regulating Microglia Polarity

Alzheimer’s disease(AD)has attracted more and more attention due to the heavy burden on families and society,as well as the gradually increasing incidence.Some studies have found that the content of CHIT1 in cerebrospinal fluid of AD patients is significantly increased,but the specific mechanism of CHIT1 in AD is still unclear.In this study,the APP/PS1 transgenic mice,microglia treated with Aβoligomer and neurons co-cultured with it were studied.Proteomics,cerebral blood flow,MRI,patch clamp and flow cytometry were used in this study.Morris Water Maze,Y maze,Novel object recognition and other behavioral experiments were also conducted.In addition,q RT-PCR,WB,immunohistochemistry,Transwell,Tunel staining,Niger staining,HE staining and other experimental methods were also used in this study to explore the mechanism of CHIT1 affecting the occurrence and development of AD by regulating the polarity and function of microglia.The results showed that :(1)CHIT1 increased the rate of change of cerebral blood flow,improved spatial memory and learning ability,improved cognitive function,and reduced hippocampal atrophy in AD mice.(2)In the pathological state of AD,CHIT1 could regulate the transformation of microglia from M1(anti-inflammatory)to M2(pro-inflammatory)phenotype,down-regulate the expression of pro-inflammatory factors such as CD68,IL-6,IL-1β and TNF-α,and up-regulate the expression of anti-inflammatory factors such as Arginas 1,CD206,IL-4 and Ym1 by IDH1.CHIT1 promoted the phagocytosis and migration of microglia,promote the phagocytosis of Aβ by microglia,and up-regulate the expression of TREM2 and other related phagoreceptors.CHIT1 also reduced K+ mediated current influx induced by Aβ stimulation and inhibited microglial overactivation induced by external stimulation.(3)CHIT1 enhanced neuronal activity through microglia and inhibit neuronal apoptosis in AD by up-regulating anti-apoptotic factor Bcl-2 and down-regulating pro-apoptotic factor Bax,Caspase 3 and Caspase 9.(4)IDH1 may be a key downstream target protein that CHIT1 regulates microglia polarity,promotes microglia phagocytosis,and inhibits neuronal apoptosis through microglia in AD pathology.Our study demonstrates that CHIT1 may be a potential target for the diagnosis and treatment of AD,providing new ideas for the treatment of AD.