Amyloidosis associated proteins in Alzheimer’s disease pathogenesis

总结 令人信服的数据支持当代版本的淀粉样蛋白级联假说（ACH）作为一个有效的框架， 了解AD发病机制和疾病改善疗法的发展。然而，ACH的关键方面 并没有得到很好的理解。其中一个方面是聚集的Aβ和神经变性之间的关系。 关于这种关系的主流概念是Aβ聚集体直接具有神经毒性和/或触发毒性反应。 神经胶质反应然而，大量的观察表明，Aβ积累和神经退行性变之间的联系， 可能更复杂。作为直接Aβ聚集体“毒素”模型的工作假设和非排他性机制， 我们提出，大量的生物活性蛋白质，我们将称为淀粉样蛋白相关蛋白（AAP）， 在大脑中以Aβ沉积物的形式积累。因此，Aβ聚集体蓄积可能没有足够的毒性来诱导 下游神经变性，除非伴随AAP积累。事实上，在这种情况下， 有助于触发AD的神经退行性阶段，解释了Aβ沉积发作和 人类的神经退化拟议的研究将利用AMP-AD倡议和其他 已经发表的研究使用最先进的蛋白质组学来鉴定大量的候选AAP， 在AD和Aβ沉积的小鼠模型中。这些候选AAP中的许多具有已知或推断的小区信令 功能协调发展的此外，对于一些候选AAP，先前的数据表明它们与AD相关， 或者我们已经产生了新的数据显示老年斑的积累。最后，正如其他人对AAPs的研究所示，ApoE 和丛生蛋白，我们发现选择AAP（中期因子，多效生长因子）的表达调节淀粉样蛋白沉积。建立在 根据这些初步数据，我们提出了三个旨在探索我们的全球假设的目标。在目标1中，我们将评估 AAP在AD和小鼠淀粉样蛋白沉积模型中的时空积累。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蛋白斑块的关联，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， Aβ。在目标3中，我们打算探索AAP与斑块相关的机制以及这种相关性如何 可能会改变AAP的生物学特性。

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.