Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP/PS1 mouse model
- 1.9k Downloads
Clearance of amyloid-beta (Aβ) from the brain is an important therapeutic strategy for Alzheimer’s disease (AD). Current studies mainly focus on the central approach of Aβ clearance by introducing therapeutic agents into the brain. In a previous study, we found that peripheral tissues and organs play important roles in clearing brain-derived Aβ, suggesting that the peripheral approach of removing Aβ from the blood may also be effective for AD therapy. Here, we investigated whether peritoneal dialysis, a clinically available therapeutic method for chronic kidney disease (CKD), reduces brain Aβ burden and attenuates AD-type pathologies and cognitive impairments. Thirty patients with newly diagnosed CKD were enrolled. The plasma Aβ concentrations of the patients were measured before and after peritoneal dialysis. APP/PS1 mice were subjected to peritoneal dialysis once a day for 1 month from 6 months of age (prevention study) or 9 months of age (treatment study). The Aβ in the interstitial fluid (ISF) was collected using microdialysis. Behavioural performance, long-term potentiation (LTP), Aβ burden and other AD-type pathologies were measured after 1 month of peritoneal dialysis. Peritoneal dialysis significantly reduced plasma Aβ levels in both CKD patients and APP/PS1 mice. Aβ levels in the brain ISF of APP/PS1 mice immediately decreased after reduction of Aβ in the blood during peritoneal dialysis. In both prevention and treatment studies, peritoneal dialysis substantially reduced Aβ deposition, attenuated other AD-type pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, and synaptic dysfunction, and rescued the behavioural deficits of APPswe/PS1 mice. Importantly, the Aβ phagocytosis function of microglia was enhanced in APP/PS1 mice after peritoneal dialysis. Our study suggests that peritoneal dialysis is a promising therapeutic method for AD, and Aβ clearance using a peripheral approach could be a desirable therapeutic strategy for AD.
KeywordsAlzheimer’s disease Amyloid-beta Peritoneal dialysis Neurodegeneration Peripheral clearance
This study was supported by National Natural Science Foundation of China (Grant Number 81471296 and 81625007). W.S. is the holder of the Tier 1 Canada Research Chair in Alzheimer’s Disease.
Compliance with ethical standards
Conflict of interest
The authors declare no conflicts of interest.
- 15.Henderson SJ, Andersson C, Narwal R, Janson J, Goldschmidt TJ, Appelkvist P et al (2013) Sustained peripheral depletion of amyloid-beta with a novel form of neprilysin does not affect central levels of amyloid-beta. Brain 137:553–64. doi: 10.1093/brain/awt308 CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Iijima-Ando K, Hearn SA, Granger L, Shenton C, Gatt A, Chiang HC et al (2008) Overexpression of neprilysin reduces alzheimer amyloid-beta42 (Abeta42)-induced neuron loss and intraneuronal Abeta42 deposits but causes a reduction in cAMP-responsive element-binding protein-mediated transcription, age-dependent axon pathology, and premature death in Drosophila. J Biol Chem 283:19066–19076. doi: 10.1074/jbc.M710509200 CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Kitaguchi N, Hasegawa M, Ito S, Kawaguchi K, Hiki Y, Nakai S et al (2015) A prospective study on blood Abeta levels and the cognitive function of patients with hemodialysis: a potential therapeutic strategy for Alzheimer’s disease. J Neural Transm (Vienna, Austria: 1996) 122:1593–1607. doi: 10.1007/s00702-015-1431-3 CrossRefGoogle Scholar
- 32.Pipili C, Polydorou A, Pantelias K, Korfiatis P, Nikolakopoulos F, Grapsa E (2013) Improvement of hepatic encephalopathy by application of peritoneal dialysis in a patient with non-end-stage renal disease. Perit Dial Int 33:213–216. doi: 10.3747/pdi.2011.00271 CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Sakai K, Senda T, Hata R, Kuroda M, Hasegawa M, Kato M et al (2016) Patients that have undergone hemodialysis exhibit lower amyloid deposition in the brain: evidence supporting a therapeutic strategy for Alzheimer’s disease by removal of blood amyloid. J Alzheimers Dis 51:997–1002. doi: 10.3233/JAD-151139 CrossRefPubMedGoogle Scholar
- 36.Sehgal N, Gupta A, Valli RK, Joshi SD, Mills JT, Hamel E et al (2012) Withania somnifera reverses Alzheimer’s disease pathology by enhancing low-density lipoprotein receptor-related protein in liver. Proc Natl Acad Sci USA 109:3510–3515. doi: 10.1073/pnas.1112209109 CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Walker JR, Pacoma R, Watson J, Ou W, Alves J, Mason DE et al (2013) Enhanced proteolytic clearance of plasma Abeta by peripherally administered neprilysin does not result in reduced levels of brain Abeta in mice. J Neurosci 33:2457–2464. doi: 10.1523/JNEUROSCI.3407-12.2013 CrossRefPubMedGoogle Scholar