Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.
Department of Nephrology, Daping Hospital, Third Military Medical University, Chongqing, China.
Acta Neuropathol. 2017 Aug;134(2):207-220. doi: 10.1007/s00401-017-1721-y. Epub 2017 May 5.
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.
清除脑内淀粉样蛋白-β（Aβ）是治疗阿尔茨海默病（AD）的重要策略。目前的研究主要集中在通过将治疗剂引入大脑来清除 Aβ 的中枢方法上。在之前的一项研究中，我们发现外周组织和器官在清除脑源性 Aβ方面发挥着重要作用，这表明从血液中清除 Aβ 的外周方法也可能对 AD 治疗有效。在这里，我们研究了腹膜透析（一种用于治疗慢性肾脏病（CKD）的临床可用治疗方法）是否可以减轻脑 Aβ负担并减轻 AD 型病理和认知障碍。我们招募了 30 名新诊断为 CKD 的患者。在腹膜透析前后测量了患者的血浆 Aβ 浓度。APP/PS1 小鼠从 6 个月龄（预防研究）或 9 个月龄（治疗研究）开始每天接受腹膜透析一次，持续 1 个月。使用微透析收集间质液（ISF）中的 Aβ。腹膜透析 1 个月后测量行为表现、长时程增强（LTP）、Aβ 负担和其他 AD 型病理。腹膜透析显著降低了 CKD 患者和 APP/PS1 小鼠的血浆 Aβ 水平。在腹膜透析降低血液中的 Aβ 后，APP/PS1 小鼠的脑 ISF 中的 Aβ 水平立即降低。在预防和治疗研究中，腹膜透析均显著减少了 Aβ 沉积，减轻了其他 AD 型病理，包括 Tau 过度磷酸化、神经胶质激活、神经炎症、神经元丢失和突触功能障碍，并挽救了 APPswe/PS1 小鼠的行为缺陷。重要的是，腹膜透析后 APP/PS1 小鼠的小胶质细胞 Aβ 吞噬功能增强。我们的研究表明，腹膜透析是治疗 AD 的一种有前途的治疗方法，使用外周方法清除 Aβ 可能是治疗 AD 的理想策略。
