Aβ外周清除功能在阿尔茨海默病发生中的作用和机制研究

Overproduction of amyloid-beta(Abeta) and reduced clearance of Abeta deposition in the brain play critical roles in the development of Alzheimer's disease (AD). Removal of brain Abeta deposition is a major therapeutic strategy for AD. Previously we classified the Abeta clearane into central clearance and periperal clearance based on the action site of Abeta-removal agents.Immunotherapy, which targets Abeta clearance, failed in clinical trials, with a series of adverse effects, which were associated with the entry of antibodies into the brain. Thus we proposed that peripheral clearance would be a safer and effective approach to remove Abeta from the brain. The periphal organs and tissues, such as liver, kidney and blood phagocytes, have natural abilities to degrade Abeta from the blood. However, the roles the natural peripheral Abeta clearance in the development of AD, and the underlying mechanisms, remains largely unknown. In addition, Abeta is also produced in peripheral tissues and organs, it is unknown whether this periphery originated Abeta can enter brain and contribute to Abeta deposition in the brain of AD remains unknown. In the present proposal, firstly we will investigate the ability of Abeta clearance in peripheral tissues and organs, and elucidate the relevant mechanisms and impact of aging and gender which are important risk factors for AD. Next,we will study the contribution of peripheal Abeta clearance ability to the accumulation of Abeta deposition in the brain of AD mice by using a parabiosis model which pairs APPswe/PS1dE9 mice and wild type mice. At last we will exam whether Abeta from the paired APPswe/PS1dE9 mouse can enter the brain of paired wild type mice and form Abeta deposition in the brain. The present proposal is important to elucidate the pathogenesis of AD,and to develop novel therapies based on peirpheral Abeta clearance.

β淀粉样肽(Aβ)在脑内产生过多和/或清除障碍是阿尔茨海默病(AD)发生的主要原因。清除脑内Aβ是AD防治的重要策略。我们把Aβ清除划分为中枢清除和外周清除(Nat Rev Neurol2012),前者指Aβ清除物质进入脑内发挥清除作用,后者指通过清除血液中Aβ而促进脑内Aβ外流和清除。针对Aβ清除的免疫治疗临床试验均失败,其副作用与中枢清除有关,我们提出外周清除是更为安全的防治策略(Nat Rev Neurol2014)。机体具有天然Aβ外周清除能力,但机制及对AD发生的作用不清楚。外周组织产生的Aβ是否进入脑内促进AD发生值得探讨。本项目首先探讨机体外周Aβ清除能力、影响因素及机制;采用APPswe/PS1dE9小鼠和野生型小鼠并联模型,探讨天然Aβ外周清除功能在AD发生中的作用和机制,探讨外周来源Aβ是否促进AD发生。本项目从外周角度探讨AD发生机制,对建立AD防治新策略有重要意义。

β淀粉样肽（Aβ）是阿尔茨海默病（Alzheimer's disease, AD）的核心致病物质。Aβ产生和清除平衡障碍导致脑内Aβ过度沉积，被认为是散发型AD(约占全部AD的99%)主要的发病原因。清除脑内Aβ是AD防治的重要策略，过去的研究聚焦于使药物进入脑内发挥Aβ清除作用，但在临床试验中抗Aβ抗体进入脑内可诱发自身免疫性脑炎等一系列中枢神经损害。从中枢以外途径来清除脑内Aβ是一个值得探讨的重要研究方向，因此本项目探讨了生理性Aβ外周清除的机制和AD防治作用，我们的研究明确了：1）生理条件下外周系统具有清除脑内Aβ的能力。Aβ从脑内流出到外周血液，经过上腔静脉、右心、肺循环、左心、体循环以后，被所经过的外周脏器及组织清除。腹腔脏器在脑内Aβ的外周清除中发挥着重要作用，尤其是肝脏、肾脏、胃肠道和皮肤可能是Aβ外周清除的主要脏器。2）Aβ外周清除能力显著降低AD脑内Aβ水平。Aβ外周清除能力显著减少AD脑实质及脑血管内Aβ水平。并且Aβ外周清除能力不影响AD脑内Aβ的产生和中枢清除。外周脏器组织在清除脑内Aβ中具有重要作用，经过计算约40%脑内Aβ经由外周脏器和组织进行清除。上述结果同时也提示，外周脏器及组织Aβ清除能力的下降可能是AD发生的原因。3）Aβ外周清除能力显著改善AD相关病理特征。Aβ外周清除能力显著减轻AD脑内小胶质细胞和星形胶质细胞活化，降低脑内细胞因子水平，减轻Tau蛋白的过度磷酸化。同时，Aβ外周清除能力显著减轻AD脑内神经元缺失、凋亡和突触变性坏死。因此，外周系统是清除脑内Aβ、减轻AD相关病理改变的有效途径。增加外周脏器和组织Aβ清除能力，可能有助于延缓AD的发生发展。4）利用腹膜透析发展了从外周途径来安全清除脑内Aβ的新策略，为今后外周途径清除Aβ的临床应用奠定了基础。