1. Physiological clearance of amyloid-beta by the kidney and its therapeutic potential for Alzheimer’s disease
- Author
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Ding-Yuan Tian, Hongwen Zhao, Xian-Le Bu, Chen-Yang He, Mao-Zhi Tang, Dong-Yu Fan, Hao-Lun Sun, Yan-Jiang Wang, Ying-Ying Shen, Pu-Yang Sun, Gui-Hua Zeng, Cheng-Rong Tan, Xue-Lian Hu, Jun Wang, Yuan Cheng, Zhong-Yuan Yu, Ye-Ran Wang, Si-Han Chen, Qian-Guang Pan, and Zhen-Qian Zhuang
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Amyloid beta ,Mice, Transgenic ,Kidney ,Pathogenesis ,Amyloid beta-Protein Precursor ,Mice ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Alzheimer Disease ,Internal medicine ,medicine.artery ,Presenilin-1 ,Animals ,Medicine ,Renal artery ,Molecular Biology ,Neuroinflammation ,Amyloid beta-Peptides ,biology ,business.industry ,Brain ,Furosemide ,Pathophysiology ,Disease Models, Animal ,Psychiatry and Mental health ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,biology.protein ,Renal vein ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Amyloid-β (Aβ) 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 Aβ produced in the brain is cleared by transport into the periphery. However, the mechanism and pathophysiological significance of peripheral Aβ clearance remain largely unknown. The kidney is thought to be responsible for Aβ clearance, but direct evidence is lacking. In this study, we investigated the impact of unilateral nephrectomy on the dynamic changes in Aβ 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 Aβ clearance via the kidney were assessed. We detected Aβ in the kidneys and urine of both humans and animals and found that the Aβ level in the blood of the renal artery was higher than that in the blood of the renal vein. Unilateral nephrectomy increased brain Aβ 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 Aβ levels and attenuated AD pathologies and cognitive deficits in APP/PS1 mice. Our findings demonstrate that the kidney physiologically clears Aβ from the blood, suggesting that facilitation of Aβ clearance via the kidney represents a novel potential therapeutic approach for AD.
- Published
- 2021