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

Pb 在脑淀粉样血管病中的致病作用和 AD 补充剂

• 批准号: 10464041
• 负责人: YANSHENG DU
• 金额: $ 19.24万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10464041
• 关键词: APP-PS1; Administrative Supplement; Age-Months; Agreement; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Amyloid deposition; Antibodies; Astrocytes; Binding; Biological Assay; Blood Vessels; Brain; Cerebral Amyloid Angiopathy; Cerebral hemisphere hemorrhage; Cerebrovascular system; Data; Deposition; Development; Diagnosis; Diagnostic Procedure; Drainage procedure; Etiology; Female; Fibronectins; Funding; Gender; Hemorrhage; Hour; Human; Image; Immunohistochemistry; Immunotherapy; Infarction; Inflammation; Institutes; Intravenous Immunoglobulins; Lead; Left; Leptomeninges; Literature; Litter Size; Lobar; Longitudinal Studies; Magnetic Resonance Imaging; Mediating; Microglia; Molecular; Mus; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Patients; Phase; Phenotype; Plasminogen Activator Inhibitor 1; Positron-Emission Tomography; Prevention; Public Health; Publishing; Research; Rest; Risk Factors; Role; Senile Plaques; Suggestion; Testing; Time; TimeLine; Transforming Growth Factors; Transgenic Mice; Wit; Work; base; brain parenchyma; cerebral capillary; cerebral microbleeds; cerebral microinfarct; cost; design; experimental study; ferumoxtran; follow-up; imaging study; inhibitor; ischemic lesion; lead exposure; male; news; novel; novel strategies; overexpression; parent grant; tv watching

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.

项目摘要 β淀粉样蛋白（Aβ）不仅以老年斑（SP）的形式存在于脑实质中， 存在于脑毛细血管中;后者被定义为脑淀粉样血管病（CAA），这是一种 阿尔茨海默病（Alzheimer disease，AD）是公认的阿尔茨海默病（Alzheimer disease，AD）的突出病理特征。CAA偶尔发生， 在大约85%-95%的AD患者中观察到。晚期CAA导致自发性肺叶切除 脑梗死和缺血性病变/梗死。与主要由Aβ1-42组成的SP相比，CAA 主要含有Aβ1-40。通过改变植物中可溶性固形物和CAA的比例， Aβ1-42和Aβ1-40。人apoEe 4是一种散发性AD的危险因子，与SP相比，它也促进了CAA的形成。 CAA介导的出血与活化的小胶质细胞和星形胶质细胞密切相关11。最近， 许多Aβ免疫疗法显示增加与淀粉样蛋白负载相关的脑微血管病变， 血管，虽然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SP和CAA介导的AD发展。目前，铅仍然是一个主要的公共卫生问题， 关心我们发现铅暴露升高并保持脑Aβ40/42的高比例，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（TGF-β）过度表达， CAA形成的因素，发现在软脑膜。因此，我们建议测试两个样品中的Pb 不同的APP转基因小鼠系能够诱导炎症相关的CAA，导致脑 通过使用USPIO MRI/18F-AV 45 PET和免疫组织化学（IHC）进行微血管造影，以及Pb诱导的 CAA是TGF-β1诱导派和纤维连接蛋白表达，破坏血管周围引流的结果 和/或增强Aβ与血管系统的结合。此外，人抗A β抗体和TM 5275，a 派-1的特异性抑制剂，将用于进一步测试我们的假设。我们相信我们的假设会揭示， 首次在文献中，CAA，独立于SP，作为铅介导的AD的负责机制 发病机制/发展，这项研究将提供机会，发展早期诊断方法 和有效的抗A β治疗AD。

项目成果

Pharmacokinetic, pharmacodynamic, and transcriptomic analysis of chronic levetiracetam treatment in 5XFAD mice: A MODEL-AD preclinical testing core study.

• DOI: 10.1002/trc2.12329
• 发表时间: 2022
• 期刊: ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS
• 影响因子: 4.8
• 作者: Onos, Kristen D;Quinney, Sara K;Jones, David R;Masters, Andrea R;Pandey, Ravi;Keezer, Kelly J;Biesdorf, Carla;Metzger, Ingrid F;Meyers, Jill A;Peters, Johnathon;Persohn, Scott C;McCarthy, Brian P;Bedwell, Amanda A;Figueiredo, Lucas L;Cope, Zackary A;Sasner, Michael;Howell, Gareth R;Williams, Harriet M;Oblak, Adrian L;Lamb, Bruce T;Carter, Gregory W;Rizzo, Stacey J Sukoff;Territo, Paul R
• 通讯作者: Territo, Paul R