肝脏对 β-淀粉样蛋白的生理清除及其对阿尔茨海默病的治疗潜力,Acta Neuropathologica

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肝脏对 β-淀粉样蛋白的生理清除及其对阿尔茨海默病的治疗潜力
Acta Neuropathologica ( IF 9.3 ) Pub Date : 2023-03-25 , DOI: 10.1007/s00401-023-02559-z
Yuan Cheng _{1,

2,

3,

4,

5} , Chen-Yang He _{1,

2,

3,

6} , Ding-Yuan Tian _{1,

7} , Si-Han Chen _{1,

2,

3} , Jun-Rong Ren _{1,

2,

3} , Hao-Lun Sun _{1,

8} , Man-Yu Xu _{1,

2,

3} , Cheng-Rong Tan _{1,

2,

3} , Dong-Yu Fan _{1,

8} , Jie-Ming Jian _{1,

2,

3} , Pu-Yang Sun _{1,

2,

3} , Gui-Hua Zeng _{1,

2,

3} , Ying-Ying Shen _{1,

2,

3} , An-Yu Shi _{1,

2,

3} , Wang-Sheng Jin _{1,

2,

3} , Xian-Le Bu _{1,

2,

3} , Hong-Ming Liu ₉ , Yu-Ming Xu ₁₀ , Jun Wang _{1,

2,

3} , Yan-Jiang Wang _{1,

2,

3,

11,

12,

13}

Affiliation

Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.
Institute of Brain and Intelligence, Third Military Medical University, Chongqing, China.
Chongqing Key Laboratory of Ageing and Brain Diseases, Chongqing, China.
Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
National Center for Neurological Disorders, Shanghai, China.
Department of Neurology, The General Hospital of Western Theater Command, Chengdu, 610000, China.
Department of Cardiology, Southwest Hospital, Third Military Medical University, Chongqing, China.
Shigatse Branch, Xinqiao Hospital, Third Military Medical University, Shigatse, China.
Department of Hepatobiliary Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China.
Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing, China.
Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
State Key Laboratory of Trauma, Burns, and Combined Injury, Third Military Medical University, Chongqing, China.

由于 Aβ 清除受损导致的脑淀粉样蛋白-β (Aβ) 积累是阿尔茨海默病 (AD) 发病机制中的关键事件。相当多的脑源性 Aβ 通过输送到外周被清除。肝脏是负责清除外周代谢物的最大器官。肝脏是否生理清除循环 Aβ 及其对 AD 的治疗潜力仍不清楚。在这里，我们发现大约 13.9% 的 Aβ42 和 8.9% 的 Aβ40 在流经肝脏时从血液中去除，并且这种能力随着老年动物肝细胞中 Aβ 受体 LRP-1 表达的下调而降低。肝血流的部分阻塞增加了血液和脑间质液中的 Aβ 水平。通过肝细胞特异性 LRP-1 敲除导致肝脏 Aβ 清除率的慢性下降加重了大脑 Aβ 负担和认知缺陷，而通过 LRP-1 过表达增强肝脏 Aβ 清除率减轻了 APP/PS1 小鼠的大脑 Aβ 沉积和认知障碍。我们的研究结果表明，肝脏在生理上清除血液中的 Aβ 并调节大脑中的 Aβ 水平，这表明衰老过程中肝脏 Aβ 清除率的下降可能与 AD 的发展有关，而肝脏 Aβ 清除率是 AD 的一种新型治疗方法。

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Physiological β-amyloid clearance by the liver and its therapeutic potential for Alzheimer’s disease

Cerebral amyloid-β (Aβ) accumulation due to impaired Aβ clearance is a pivotal event in the pathogenesis of Alzheimer’s disease (AD). Considerable brain-derived Aβ is cleared via transporting to the periphery. The liver is the largest organ responsible for the clearance of metabolites in the periphery. Whether the liver physiologically clears circulating Aβ and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Aβ42 and 8.9% of Aβ40 were removed from the blood when flowing through the liver, and this capacity was decreased with Aβ receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Aβ levels in both blood and brain interstitial fluid. The chronic decline in hepatic Aβ clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Aβ burden and cognitive deficits, while enhancing hepatic Aβ clearance via LRP-1 overexpression attenuated cerebral Aβ deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Aβ and regulates brain Aβ levels, suggesting that a decline of hepatic Aβ clearance during aging could be involved in AD development, and hepatic Aβ clearance is a novel therapeutic approach for AD.

更新日期：2023-03-26

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