Sorl1, also known as LR11, is a type I transmembrane protein belonging to both the low-density lipoprotein receptor (LDLR) family and the vacuolar protein sorting 10 (VPS10) domain receptor family. It is genetically implicated in Alzheimer's disease (AD) and impacts amyloid precursor protein (APP) trafficking. Acting with the retromer trafficking complex, it regulates endosomal recycling of multiple transmembrane proteins related to AD pathophysiology, and is involved in lipid-related pathways through regulating APOE and CLU levels [1,2,3].

Sorl1-null induced pluripotent stem cells differentiated into different cell types show that Sorl1 loss leads to diverse pathway alterations, with the greatest effects in neurons and astrocytes. In neurons, it specifically reduces APOE and CLU and alters lipid profiles. Sorl1-knockout mouse models display learning and memory deficits, down-regulation of brain-derived neurotrophic factor in the hippocampus and cortex, and amyloid β-protein deposits. Hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice are impaired, with reduced expression and colocalization of synaptic proteins [2,4].

In conclusion, Sorl1 is a key regulator in endosomal degradation and recycling pathways in neurons, and its loss-of-function significantly impacts AD-related biological processes. The use of gene-knockout models, especially Sorl1-KO mouse models, has revealed its crucial role in AD pathogenesis, providing insights for understanding the disease mechanism and potential therapeutic development for AD.