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.

概括令人信服的数据支持当代版本的淀粉样蛋白级联假说 (ACH) 作为有效框架了解 AD 发病机制和疾病缓解疗法的发展然而，ACH 的关键方面。其中一个方面是聚集的 Aβ 的积累与神经退行性变之间的关系。关于这种关系的主流概念是 Aβ 的聚集体具有直接的神经毒性和/或引发毒性。然而，大量观察表明 Aβ 积累与神经退行性变之间存在联系。作为直接 Aβ 聚集“毒素”模型的工作假设和非排他性机制，可能更为复杂。我们提出大量的生物活性蛋白，我们将其称为淀粉样蛋白相关蛋白（AAP）作为 Aβ 沉积物在大脑中积累，因此，Aβ 聚集体的积累可能不足以引起诱导。除非伴有 AAP 积累，否则下游神经变性确实，在这种情况下 AAP 会积累。有助于触发 AD 的神经退行性阶段，解释了 Aβ 沉积开始和拟议的研究将利用来自 AMP-AD 计划和其他项目的大量数据。已发表的研究使用最先进的蛋白质组学来鉴定大量增加的候选 AAP 在 AD 和 Aβ 沉积的小鼠模型中，许多候选 AAP 具有已知或推断的细胞信号传导。此外，对于某些候选 AAP，有先前的数据表明它们与 AD 相关。或者我们已经生成了显示老年斑中积累的新数据，正如其他人针对 AAP、ApoE 所显示的那样。和簇蛋白，我们发现特定 AAP（中期因子、多效蛋白）的表达可调节淀粉样蛋白沉积。根据初步数据，我们提出了三个目标，旨在探讨我们的全球假设。在目标 1 中，我们将评估目标。 AD 和淀粉样蛋白沉积小鼠模型中 AAP 的时空积累在目标 2 中，我们将使用 rAAV-。在 APP 小鼠模型中介导 AAP 的表达，以 a) 进一步评估与淀粉样斑块的关联，b) 确定表达是否改变淀粉样蛋白沉积并影响其他 AD 相关病理，独立于对在目标 3 中，我们打算探索 AAP 与斑块结合的机制以及这种结合的方式。可能会改变 AAP 的生物学特性。