权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要令人信服的数据支持当代版本的淀粉样级联假说(ACH)，作为一种有效的框架了解阿尔茨海默病的发病机制和疾病调节疗法的发展。然而，ACH的关键方面都没有被很好地理解。其中一个方面是聚集的A-β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的聚集体直接具有神经毒性和/或引发毒性神经胶质反应。然而，大量观察表明，Aβ积聚和神经退行性变之间的联系可能会更复杂。作为对直接Aβ聚合体“毒素”模型的工作假设和非排他性机制，我们提出了大量的生物活性蛋白，我们将称之为淀粉样蛋白相关蛋白(AAPS)。随着Aβ的沉积在大脑中积聚。因此，β聚集可能没有足够的毒性来诱导下游神经变性，除非伴有AAP积聚。事实上，在这种情况下，AAPS的积累有助于触发AD的神经退行性变阶段，解释了Aβ沉积开始和人类的神经变性。拟议的研究将利用AMP-AD倡议和其他已发表的研究使用最先进的蛋白质组学来识别大量增加的候选AAP 在AD和Aβ沉积的小鼠模型中都有。这些候选AAP中的许多已经知道或推断出细胞信号功能。此外，对于一些候选AAP，或者存在表明它们与AD相关联的先前数据或者，我们已经产生了新的数据，显示在衰老斑块中积累。最后，正如其他人为AAPS所示，ApoE 和Clusterin，我们发现选择的AAPS(中期因子，多核营养素)的表达调节淀粉样蛋白的沉积。盖楼这一初步数据，我们提出了三个目标，旨在探索我们的全球假说。在目标1中，我们将评估阿尔茨海默病和小鼠淀粉样蛋白沉积模型中AAPS的时空积累。在目标2中，我们将使用rAAV- 在APP小鼠模型中介导的AAPS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，而不依赖于对一辆β。在目标3中，我们打算探索AAP与斑块相关联的机制以及这种关联是如何可能会改变AAP的生物学特性。