摘要Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer's disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellular β-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer's disease,in this study,we established a mouse model of Sorl1 gene knockout using clustered regularly interspaced short palindromic repeats-associated protein 9 technology.We found that Sor/1-knockout mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and cortex,and amyloidβ-protein deposits were observed in the brains of Sor/1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sor/1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer's disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.