Preliminary Study Of PICALM And GAB2 In Al-induced Dementia

Alzheimer’s disease（AD）is the most common neurodegenerative disease in the world.Its pathological features are senile plaques and neurofibrillary tangles formed by amyloid（Aβ）deposition.Its clinical features are progressive memory loss,language and speech defects,impaired executive function,and daily activity disorders.At present,the pathogenesis of Alzheimer’s disease is not fully understood,which is developed from the complex interaction between heredity and environment.Both PICALM and GAB2 are susceptible genes for delayed Alzheimer’s disease.In this experiment,the knockout models of PICALM and GAB2 were established by Crispr/Cas9 technology,which provided a zebrafish Alzheimer’s disease model for mechanism research and drug screening.The details are as follows:1.The establishment of PICALM gene knockout zebrafish AD model and GAB2 gene knockout zebrafish AD model.Zebrafish PICALM and GAB2 genomic DNA exon sequences and their functional areas were searched using the Ensemble website,and PICALM and GAB2 gene knock-out targets were designed through the Zi Fi T Targeter website.After 3 generations of screening,the homozygous strain was selected.2.The role of PICALM gene and GAB2 gene in Alzheimer’s disease was studied in combination with Al Cl₃-induced zebrafish AD.Al Cl₃ induces glial cells to produce inflammatory cytokines,thereby inducing the phosphorylation of tau protein and promoting Aβdeposition.The knockout PICALM zebrafish without acid Al Cl₃ exposure was not different from the wild type,while the knockout PICALM zebrafish treated with acid Al Cl₃ alleviated the spatial memory im-pairment caused by acid Al Cl₃ in zebrafish.Therefore,it is speculated that PICALM knockout zebrafish can reduce the degree of tau protein phosphorylation and Aβdepo-sition by reducing the m RNA level of inflammatory factors,so as to reduce the degree of spatial memory impairment caused by acidic Al Cl₃ in zebrafish.The study found that knockout of GAB2 caused spatial memory impairment in zebrafish,and the degree of spatial memory impairment was higher than that of wild-type zebrafish treated with Al Cl₃.GAB2 is the main activator of phosphatidylinositol3-kinase（PI3K）signaling pathway.It is speculated that the GAB2 action point is up-stream of the Al-induced AD action point.By down-regulating the m RNA expression level of PSEN1,inhibiting the PI3K/Akt pathway,up-regulating the m RNA expression level of inflammatory factors,promoting the hyperphosphorylation of Gsk3,and then promoting the hyperphosphorylation of tau protein,zebrafish produce spatial memory impairment.In summary,PICALM knockout may reduce the degree of acid Al Cl₃-induced spatial memory impairment in zebrafish,and GAB2 knockout may cause spatial memory im-pairment in zebrafish.