期刊
MOLECULAR PSYCHIATRY
卷 26, 期 10, 页码 6074-6082出版社
SPRINGERNATURE
DOI: 10.1038/s41380-021-01073-6
关键词
-
资金
- National Natural Science Foundation of China [91749206, 81930028, 81625007, 31921003]
This study investigated the impact of unilateral nephrectomy on Aβ clearance in both humans and animals, finding that the kidney plays a physiological role in clearing Aβ. Furthermore, chronic furosemide treatment was shown to reduce Aβ levels in the blood and brain, attenuate AD pathologies, and improve cognitive deficits in APP/PS1 mice. These findings suggest that facilitation of Aβ clearance via the kidney could be a novel potential therapeutic approach for AD.
Amyloid-beta (A beta) accumulation in the brain is a pivotal event in the pathogenesis of Alzheimer's disease (AD), and its clearance from the brain is impaired in sporadic AD. Previous studies suggest that approximately half of the A beta produced in the brain is cleared by transport into the periphery. However, the mechanism and pathophysiological significance of peripheral A beta clearance remain largely unknown. The kidney is thought to be responsible for A beta clearance, but direct evidence is lacking. In this study, we investigated the impact of unilateral nephrectomy on the dynamic changes in A beta in the blood and brain in both humans and animals and on behavioural deficits and AD pathologies in animals. Furthermore, the therapeutic effects of the diuretic furosemide on A beta clearance via the kidney were assessed. We detected A beta in the kidneys and urine of both humans and animals and found that the A beta level in the blood of the renal artery was higher than that in the blood of the renal vein. Unilateral nephrectomy increased brain A beta deposition; aggravated AD pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, and neuronal loss; and aggravated cognitive deficits in APP/PS1 mice. In addition, chronic furosemide treatment reduced blood and brain A beta levels and attenuated AD pathologies and cognitive deficits in APP/PS1 mice. Our findings demonstrate that the kidney physiologically clears A beta from the blood, suggesting that facilitation of A beta clearance via the kidney represents a novel potential therapeutic approach for AD.
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