Sorl1-KO Mouse

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 is a key regulator in the trafficking and processing of amyloid precursor protein (APP), contributing to endosomal degradation and recycling pathways in neurons [1,3].

Loss of SORL1 in mouse models leads to deficits in learning and memory, down-regulation of brain-derived neurotrophic factor in the hippocampus and cortex, and amyloid β-protein deposits in the brain [4]. In human induced pluripotent stem cell-derived neurons, SORL1 depletion impairs endosomal trafficking of proteins like APP, GLUA1, and TRKB, affecting endosomal recycling and neuronal activity [1]. SORL1-null induced pluripotent stem cells differentiated into different cell types show that SORL1 loss leads to neuron-specific reduction in apolipoprotein E (APOE) and clusterin (CLU) [2].

In conclusion, SORL1 plays a crucial role in endosomal trafficking and recycling in neurons, with its deficiency being closely associated with Alzheimer's disease-related phenotypes. Studies using knockout models have significantly enhanced our understanding of SORL1's functions in the context of AD, highlighting its potential as a therapeutic target for this neurodegenerative disease.