外周源性Abeta在阿尔茨海默病发生中的作用和机制研究

It is believed that amyloid β protein (Aβ) deposits in the brain of patients with Alzheimer’s disease (AD) originate from the brain itself. However, Aβ is also generated by peripheral tissues and cells, such as skeletal muscles, skin, bone and platelets. Whether peripheral Aβ contributes to brain AD-type pathologies remains largely unknown. In our preliminary experiment, using a model of parabiosis between wild type (Wt) mice and APPswe/PS1dE9 transgenic AD mice, we observed the formation of cerebral amyloid angiopathy and Aβ plaques in the wild type mice after a 12-month period of parabiosis, which were similar to those in the brains of control AD mice. Theirfore, we speculate that peripheral Aβ can enter the brain, form AD-type pathologies and cause cognitive impairment. In this project, the entry dynamics and mechanism of peripheral Aβ into brain will be investigated; Moreover, using a model of parabiosis between Wt mice and AD mice, we intend to explore the role of peripheral Aβ in inducing AD-type pathologies and cognitive impairment; In addition, we will investigate the preventive and therapeutic effect of inhibiting the entry of peripheral Aβ into brain on AD process using RAGE inhibitors or RAGE gene deletion method. The completion of this project will provide novel insight into AD pathogenesis from a systemic view, and support the development of therapies for AD by targeting Aβ metabolism in both the brain and the periphery.

传统观点认为AD患者脑内沉积的Aβ来自于脑内产生的Aβ（中枢源性），外周组织如骨骼肌、皮肤和血小板等均产生Aβ（外源性），但外周源性Aβ在AD发生中的作用尚不清楚。我们前期发现，系统疾病和外周脏器功能与Aβ代谢或AD风险密切相关，并将野生型小鼠和APP/PS1小鼠并联后发现，源于APP/PS1小鼠的Aβ可通过血液进入野生型小鼠脑内，并形成典型的淀粉样脑血管病（CAA）和Aβ斑块。基于这些发现，我们提出：外周源性Aβ可通过血脑屏障进入脑内，沉积形成Aβ斑块，并诱发AD相关病理和认知障碍，参与AD的发生。为此，本项目拟首先探讨外周源性Aβ进入脑内的动力学及机制；进一步通过并联模型，阐明外周源性Aβ进入小鼠脑内形成AD相关病理和对认知损害的影响，并揭示相关机制；最后探讨抑制外周源性Aβ进入脑内对AD的干预作用。本项目对于从系统角度来揭示AD发病机制、寻找AD防治新途径具有重要意义。