The Pathogenic Role of Pb in Cerebral Amyloid Angiopathy and AD Supplement

项目总结 淀粉样蛋白-β蛋白(A-β)不仅以老年斑(SP)的形式存在于脑实质中，而且还存在于脑实质中。 存在于大脑的毛细血管中；后者被定义为大脑淀粉样血管病(CAA)，它是一种 公认的阿尔茨海默病(AD)的突出病理特征。CAA是零星发生的， 在大约85%-95%的AD患者中观察到。晚期CAA导致自发性肺叶 出血和缺血性病变/梗塞。与主要由β1-42组成的SP相比， 主要含有Aβ1-40。通过改变以下比例，SPS和CAA水平可以互换 Aβ1-42和Aβ1-40。人类apoE4是一种散发的AD危险因子，也促进了SPS上的CAA的形成。 CAA介导的出血与激活的小胶质细胞和星形胶质细胞密切相关。最近， 许多Aβ免疫疗法被证明增加了与淀粉样蛋白相关的脑微出血 血管，尽管不是所有的免疫疗法都是一样的。似乎有不同的分子机制 潜在的SPS和CAA介导的AD发生。目前，铅仍然是一种主要的公共卫生 担忧。我们发现铅暴露增加，并保持高的脑Aβ40/42比率，这有利于CAA的形成。 此外，铅诱导的淀粉样蛋白沉积和转化生长因子-β(转化生长因子-β)的过度表达是一种风险 在软膜中发现了形成CAA的因素。因此，我们建议测试铅在两个 不同APP转基因小鼠系能够诱导炎症相关的CAA导致脑组织 USPIO MRI/18F-AV45PET和免疫组织化学(IHC)对铅中毒小鼠脑内微量出血的研究 转化生长因子-β-1诱导纤溶酶原激活物和纤维连接蛋白表达阻断血管周围引流所致的冠状动脉粥样硬化 和/或增强Aβ与脑血管系统的结合。此外，人抗Aβ抗体和TM5275，a PAI-1的特异性抑制剂将被用来进一步检验我们的假设。我们相信我们的假设将揭示， 在文献中，CAA第一次独立于SPS而成为铅介导的AD的负责机制 发病机制/发展和这项研究将为开发早期诊断方法提供机会 以及对AD有效的抗A-β疗法。

PROJECT SUMMARY Amyloid-β protein (Aβ) is not only present in brain parenchyma in the form of senile plaques (SPs), but also exists in the brain capillary vessels; the latter is defined as the cerebral amyloid angiopathy (CAA), which is a recognized prominent pathological feature of Alzheimer disease (AD). CAA occurs sporadically, being observed in approximately 85%–95% of AD patients. The advanced CAA leads to spontaneous lobar hemorrhages and ischemic lesions/infarcts. In contrast to SPs that are largely composed of Aβ1-42, the CAA contains predominately Aβ1-40. The levels of SPs and CAA are inter-exchangeable by altering the ratio of Aβ1-42 and Aβ1-40. Human apoEe4, a sporadic AD risk factor, also facilitates the formation of CAA over SPs. CAA-mediated hemorrhage is closely associated with activated microglial cells and astrocytes11. Recently, many Aβ immunotherapies were shown to increase cerebral microhemorrhages associated with amyloid-laden vessels, although not all immunotherapies are alike. It appears there are distinct molecular mechanisms underlying SPs- and CAA-mediated AD development. Currently, Pb remains to be a major public health concern. We showed Pb exposure elevated and kept high ratios of brain Aβ40/42 that favored CAA formation. Additionally, Pb-induced amyloid deposition and overexpression of transforming growth factor-β (TGF-β), a risk factor for CAA formation, were found in leptomeninges. We therefore propose to test whether Pb in two different APP transgenic mouse lines is able to induce inflammation associated CAA that leads to cerebral microhemorrhages by using USPIO MRI/18F-AV45 PET and immunohistochemistry (IHC), and the Pb-induced CAA results from TGF-β1-induced expressions of PAI and fibronectin to disrupt the perivascular drainage and/or enhance binding of Aβ to cerebrovasculature. Additionally, human anti-Aβ antibodies and TM5275, a specific inhibitor of PAI-1, will be used to further test our hypothesis. We believe that our hypothesis will reveal, for the first time in literature, the CAA, independent of SPs, as the responsible mechanism for Pb-mediated AD pathogenesis/development and this study will provide the opportunity to develop the early diagnostic method and effective anti-Aβ therapies for AD.