Abstract
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 Sorl1-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 amyloid β-protein deposits were observed in the brains of Sorl1-knockout mice. In vitro, hippocampal neuronal cell synapses from homozygous Sorl1-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.