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Physiological β-amyloid clearance by the liver and its therapeutic potential for Alzheimer's disease
Acta Neuropathol. 2023 Mar 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 11 12 13, Yan-Jiang Wang 14 15 16 17 18 19
Abstract:
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.