Endo‐Lysosomal Network Disorder Reprograms Energy Metabolism in SorL1‐Null Rat Hippocampus

Abstract Sortilin‐related receptor 1 ( SorL1 ) deficiency is a genetic predisposition to familial Alzheimer’s disease (AD), but its pathology is poorly understood. In SorL1 ‐null rats, a disorder of the global endosome‐lysosome network (ELN) is found in hippocampal neurons. Deletion of amyloid precursor protein ( APP ) in SorL1 ‐null rats could not completely rescue the neuronal abnormalities in the ELN of the hippocampus and the impairment of spatial memory in SorL1 ‐null young rats. These in vivo observations indicated that APP is one of the cargoes of SorL1 in the regulation of the ELN, which affects hippocampal‐dependent memory. When SorL1 is depleted, the endolysosome takes up more of the lysosome flux and damages lysosomal digestion, leading to pathological lysosomal storage and disturbance of cholesterol and iron homeostasis in the hippocampus. These disturbances disrupt the original homeostasis of the material‐energy‐subcellular structure and reprogram energy metabolism based on fatty acids in the SorL1 ‐null hippocampus, instead of glucose. Although fatty acid oxidation increases ATP supply, it cannot reduce the levels of the harmful byproduct ROS during oxidative phosphorylation, as it does in glucose catabolism. Therefore, the SorL1 ‐null rats exhibit hippocampal degeneration, and their spatial memory is impaired. Our research sheds light on the pathology of SorL1 deficiency in AD.