DHCR24 reverses Alzheimer’s disease-related pathology and cognitive impairment via increasing hippocampal cholesterol levels in 5xFAD mice

Acta Neuropathologica Communications

Research

Wen-bin Zhang¹  Heng-bing Zu¹  Xiao-rou Guo¹  Meng-qi Zhang¹  Yue Huang¹  Xiang-shan Yuan² 

[1] Department of Neurology, Jinshan Hospital Affiliated to Fudan University, No.1508 Long-Hang Road, Jinshan District, 201508, Shanghai, China;Department of Neurology, Jinshan Hospital Affiliated to Fudan University, No.1508 Long-Hang Road, Jinshan District, 201508, Shanghai, China;Department of Anatomy and Histoembryology, School of Basic Medical Sciences, Fudan University, 200032, Shanghai, China;State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, 200032, Shanghai, China;

关键词: Alzheimer’s disease;    24-dehydrocholesterol reductase (DHCR24);    Cholesterol;    Gene therapy;    Neuroprotection;    Neurodegeneration;    Pathogenesis;   

DOI  :  10.1186/s40478-023-01593-y

 received in 2023-04-01, accepted in 2023-05-30,  发布年份 2023

来源: Springer

【 摘 要 】

Accumulating evidences reveal that cellular cholesterol deficiency could trigger the onset of Alzheimer’s disease (AD). As a key regulator, 24-dehydrocholesterol reductase (DHCR24) controls cellular cholesterol homeostasis, which was found to be downregulated in AD vulnerable regions and involved in AD-related pathological activities. However, DHCR24 as a potential therapeutic target for AD remains to be identified. In present study, we demonstrated the role of DHCR24 in AD by employing delivery of adeno-associated virus carrying DHCR24 gene into the hippocampus of 5xFAD mice. Here, we found that 5xFAD mice had lower levels of cholesterol and DHCR24 expression, and the cholesterol loss was alleviated by DHCR24 overexpression. Surprisingly, the cognitive impairment of 5xFAD mice was significantly reversed after DHCR24-based gene therapy. Moreover, we revealed that DHCR24 knock-in successfully prevented or reversed AD-related pathology in 5xFAD mice, including amyloid-β deposition, synaptic injuries, autophagy, reactive astrocytosis, microglial phagocytosis and apoptosis. In conclusion, our results firstly demonstrated that the potential value of DHCR24-mediated regulation of cellular cholesterol level as a promising treatment for AD.

【 授权许可】

CC BY   
© The Author(s) 2023

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