Amyloidosis associated proteins in Alzheimer’s disease pathogenesis

阿尔茨海默病发病机制中的淀粉样变性相关蛋白

基本信息

批准号：
10317235
负责人：
Todd E Golde
金额：
$ 229.01万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-05 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10317235
关键词：
Accounting Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease therapy Amyloid Amyloid beta-Protein Amyloid deposition Amyloidosis Apolipoprotein E Binding Biological Biology Brain Clinical Complex Data Deposition Development Disease Economics Epidemic Future Gliosis Heparan Sulfate Proteoglycan Heparitin Sulfate Human Individual Infrastructure Laboratories Link Literature Mainstreaming Mediating Methods Modeling Nerve Degeneration Neurites Neurodegenerative Disorders Neurons Paper Pathogenesis Pathologic Pathology Phase Play Property Proteins Proteomics Publishing Recombinant adeno-associated virus (rAAV)Reporting Resources Rodent Role Senile Plaques Signal Transduction Solubility System Tauopathies Therapeutic Toxin Validation abeta accumulation abeta deposition base design digital in vivo insight midkine mouse model multiple omics neurotoxic neurotoxicity new therapeutic target novel pleiotrophin response spatiotemporal sulfated glycoprotein 2 targeted treatment tau Proteins

项目摘要

Summary Compelling data support a contemporary version of the amyloid cascade hypothesis (ACH) as a valid framework both for understanding AD pathogenesis and the development of disease modifying therapeutics. However, key aspects of the ACH are not well understood. One such aspect is the relationship between accumulation of aggregated Aβ and neurodegeneration. The mainstream concepts regarding this relationship are that aggregates of Aβ are directly neurotoxic and/or trigger a toxic glial response. However, numerous observations indicate that the link between Aβ accumulation and neurodegeneration may be more complex. As a working hypothesis and a non-exclusive mechanism to the direct Aβ aggregate “toxin” model, we propose that a large number of biologically active proteins that we will refer to as amyloid associated proteins (AAPs) accumulate in the brain as Aβ deposits. Thus, Aβ aggregate accumulation may not be sufficiently toxic to induce downstream neurodegeneration unless accompanied by AAP accumulation. Indeed, in this scenario accumulation of AAPs helps to trigger the neurodegenerative phase of AD, accounting for the long delay between onset of Aβ deposition and neurodegeneration in humans. The proposed studies will leverage extensive data from the AMP-AD initiative and other published studies that has used state of the art proteomics to identify a large number of candidate AAPs that are increased both in AD and mouse models of Aβ deposition. Many of these candidate AAPs have known or inferred cell-signaling functions. Further, for some candidate AAPs there is either previous data demonstrating that they are associated with AD or we have generated novel data showing accumulation in senile plaques. Finally, as shown by others for the AAPs, ApoE and clusterin, we find that expression of select AAPs (midkine, pleiotrophin) modulates amyloid deposition. Building off this preliminary data, we propose three aims that are designed to probe our global hypothesis. In Aim 1 we will evaluate the spatiotemporal accumulation of AAPs in AD and in mouse models of amyloid deposition. In Aim 2 we will use rAAV- mediated expression of the AAPs in APP mouse models to a) further evaluate the association with amyloid plaques, b) determine if expression alters amyloid deposition and influences other AD relevant pathologies independent of effects on Aβ. In Aim 3 we intend to explore the mechanisms by which the AAP associates with the plaque and how that association might alter the biological properties of the AAP.

概括引人入胜的数据支持淀粉样蛋白级联假设（ACH）的当代版本作为有效框架了解AD发病机理和疾病修饰疗法的发展。但是，ACH的关键方面不太了解。这样的方面是聚集Aβ和神经退行性的积累之间的关系。关于这种关系的主流概念是Aβ的聚集物直接是神经毒性和/或触发有毒的神经胶质反应。但是，许多观察结果表明Aβ积累与神经变性之间的联系可能更复杂。作为直接Aβ骨料“毒素”模型的工作假设和非排斥机制，我们建议我们将大量的生物活性蛋白称为淀粉样蛋白相关蛋白（AAP）作为Aβ沉积物积聚在大脑中。那就是Aβ聚集物的积累可能不足以诱导除非伴有AAP积累，否则下游神经变性。确实，在这种情况下AAP的积累有助于触发AD的神经退行性阶段，这是Aβ沉积发作和人类的神经变性。拟议的研究将利用AMP-AD倡议和其他的大量数据已发表的研究已使用最先进的蛋白质组学来识别大量候选AAP的增加在Aβ沉积的AD和小鼠模型中。这些候选AAP中有许多已知或推断出细胞信号功能。此外，对于某些候选AAPS，先前的数据表明它们与AD相关联或者我们生成了新的数据，显示了老年斑块中的积累。最后，如其他AAPS所示，APOE 和簇蛋白，我们发现精选的AAP（中型，多叶酸）的表达调节淀粉样蛋白沉积。建造这个初步数据，我们提出了三个旨在探讨我们的全球假设的目标。在AIM 1中，我们将评估 AAP在AD和淀粉样蛋白沉积的小鼠模型中的时空积累。在AIM 2中，我们将使用raav- APP小鼠模型中AAP的介导的表达以a）进一步评估与淀粉样蛋白斑的关联，b）确定表达是否改变淀粉样蛋白的沉积并影响其他相关病理，而与对影响的影响无关 Aβ。在AIM 3中，我们打算探索AAP与斑块关联的机制以及该关联如何可能会改变AAP的生物学特性。