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journal article·2024-11Open access

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

Yajie Wang, Yuting Yang, Ying Cai, Ayikaimaier Aobulikasimu, Yuexin Wang, Chuanwei Hu, Zhikang Miao, Yue Shao, Mengna Zhao, Yue Hu, Chang Xu, Xinjun Chen, Zhiqiang Li, Jincao Chen, Lianrong Wang, Shi Chen

Advanced Science· Volume 11· Issue 41
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Abstract

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.
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Research context

OpenAlex topics: Cellular transport and secretion · Neuroscience and Neuropharmacology Research · Retinal Development and Disorders

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Gastroenterology Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Disease Zhongnan Hospital of Wuhan University School of Pharmaceutical Sciences Wuhan University Wuhan Hubei 430071 China

Brain Center, Department of Neurosurgery, Ministry of Education Key Laboratory of Combinatorial Biosynthesis and Drug Discovery TaiKang Center for Life and Medical Sciences, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University Wuhan 430071 China

Department of Respiratory Diseases, Institute of Pediatrics Shenzhen Children's Hospital Shenzhen 518026 China

Department of Burn and Plastic Surgery Shenzhen Key Laboratory of Microbiology in Genomic Modification & Editing and Application Shenzhen Institute of Translational Medicine Medical Innovation Technology Transformation Center Shenzhen University Medical School, Shenzhen Second People's Hospital The First Affiliated Hospital of Shenzhen University Shenzhen 518035 China

Funding

National Key Research and Development Program of China · National Natural Science Foundation of China · Fundamental Research Funds for the Central Universities

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