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Physiological clearance of amyloid-beta by the kidney and its therapeutic potential for Alzheimer’s disease

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.

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Fig. 1: Physiological Aβ clearance function of the kidney.
Fig. 2: Kidney ligation increases Aβ levels in the blood and ISF in AD mice.
Fig. 3: Unilateral nephrectomy increases blood and brain Aβ burden.
Fig. 4: Unilateral nephrectomy aggravates cognitive impairments in AD mice.
Fig. 5: Furosemide treatment alleviates the Aβ burden and rescues cognitive impairments.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (91749206, 81930028, 81625007, and 31921003).

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Y.J.W., J.W., and H.W.Z. conceived and designed the project, D.Y.T., X.L.H., Y.Y.S., G.H.Z., and S.H.C. conducted patient enrolment, assessment, and sample treatment, D.Y.T., Y.C., Z.Q.Z., C.Y.H., Q.G.P, M.Z.T., Y.R.W., H.L.S., P.Y.S., Z.Y.Y., D.Y.F., X.L.B., J.W., and C.R.T. conducted animal and in vitro experiments, D.Y.T., Y.C., and C.R.T. analysed data, D.Y.T. and Y.J.W. wrote the manuscript.

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Correspondence to Jun Wang, Hong-Wen Zhao or Yan-Jiang Wang.

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Tian, DY., Cheng, Y., Zhuang, ZQ. et al. Physiological clearance of amyloid-beta by the kidney and its therapeutic potential for Alzheimer’s disease. Mol Psychiatry 26, 6074–6082 (2021). https://doi.org/10.1038/s41380-021-01073-6

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