| First Author | Cheng Y | Year | 2023 |
| Journal | Acta Neuropathol | Volume | 145 |
| Issue | 6 | Pages | 717-731 |
| PubMed ID | 36964213 | Mgi Jnum | J:348786 |
| Mgi Id | MGI:7643492 | Doi | 10.1007/s00401-023-02559-z |
| Citation | Cheng Y, et al. (2023) Physiological beta-amyloid clearance by the liver and its therapeutic potential for Alzheimer's disease. Acta Neuropathol 145(6):717-731 |
| abstractText | Cerebral amyloid-beta (Abeta) accumulation due to impaired Abeta clearance is a pivotal event in the pathogenesis of Alzheimer's disease (AD). Considerable brain-derived Abeta 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 Abeta and its therapeutic potential for AD remains unclear. Here, we found that about 13.9% of Abeta42 and 8.9% of Abeta40 were removed from the blood when flowing through the liver, and this capacity was decreased with Abeta receptor LRP-1 expression down-regulated in hepatocytes in the aged animals. Partial blockage of hepatic blood flow increased Abeta levels in both blood and brain interstitial fluid. The chronic decline in hepatic Abeta clearance via LRP-1 knockdown specific in hepatocytes aggravated cerebral Abeta burden and cognitive deficits, while enhancing hepatic Abeta clearance via LRP-1 overexpression attenuated cerebral Abeta deposition and cognitive impairments in APP/PS1 mice. Our findings demonstrate that the liver physiologically clears blood Abeta and regulates brain Abeta levels, suggesting that a decline of hepatic Abeta clearance during aging could be involved in AD development, and hepatic Abeta clearance is a novel therapeutic approach for AD. |
