UPR as a Neuronal Death Mediator in Alzheimer's Disease

描述(由申请人提供)： 与平民相比，美国退伍军人患阿尔茨海默病(AD)病理和症状的风险更高(1)。微管相关蛋白tau是AD大脑中神经元丢失的主要贡献者。正如我们最近发表的文章所显示的，我们发现了一种可能参与tau介导的AD神经毒性的新机制：激活未折叠蛋白反应(UPR)(2)。我们还发现，在转基因tau小鼠中，PERK和UPR的其他一些成分被激活。与之前的发现(3-6)一致，UPR在人类AD大脑中也被激活，证实了没有过度表达的tau积累足以激活UPR。我们发现发生这种情况的一个原因是，可溶性tau中间体可以通过与VCP/Hrd1复合体的异常相互作用来抑制内质网(ER)相关降解(ERAD)，而VCP/Hrd1复合体是正常ERAD所必需的。这种错误的相互作用导致泛素化和错误折叠的ER蛋白积累，触发UPR，我们推测这反过来有助于在tauopathy中观察到的神经元死亡。由于AD脑内神经元的死亡远远超过tau病理的负担(7)，这表明可溶性tau必须在脑内引发与可检测到的缠结病理无关的有害事件，如应激颗粒动力学中断(8)和慢性UPR激活(2)。在年轻的和老年的tau转基因小鼠中，UPR似乎是不同的，这与其他一些研究表明UPR随着年龄的变化而变化是一致的。此外，虽然UPR在某些条件下会导致细胞死亡，但它也是一种必要的级联反应，可以起到保护作用(9)。我们将评估tau和老化的神经元环境如何通过UPR级联来调节蛋白毒性。具体地说，我们将评估Tau在衰老大脑中激活UPR的特异性。我们也 将通过使用编码UPR的3个不同分支的AAV载体来确定抑制UPR是否保护神经元免受tau毒性。最后，我们将特别关注含有Valosin的蛋白(VCP/p97/CDC48)/Hrd1 ERAD复合体，确定tau抑制ERAD和触发UPR的机制。通过实验操作UPR，我们将能够确定UPR的某些方面是否对AD进展有利，而其他方面是否对AD进展不利。

DESCRIPTION (provided by applicant): U.S. Veterans are at increased risk for developing Alzheimer's disease (AD) pathologies and symptoms compared to the civilian population (1). The microtubule associated protein tau is a major contributor to the neuronal loss that occurs in the AD brain. As our recent publication shows, we have discovered a new mechanism that may be involved in tau-mediated neurotoxicity in AD: activation of the unfolded protein response (UPR)(2). We also found that PERK and some other components of the UPR are activated in transgenic tau mice. The UPR is also activated in the human AD brain, consistent with previous findings (3-6), confirming that tau accumulation without over-expression is sufficient to activate the UPR. One reason we have discovered for why this occurs is that soluble tau intermediates can inhibit endoplasmic reticulum (ER) associated degradation (ERAD) through aberrant interaction with the VCP/Hrd1 complex, which is necessary for normal ERAD. This faulty interaction causes ubiquitinated and misfolded ER proteins to accumulate, triggering the UPR, which in turn we speculate contributes to the neuronal death observed in tauopathies. Since the neuronal death in the AD brain far exceeds the burden of tau pathology (7), it suggests that soluble tau must trigger noxious events in the brain independent of detectable tangle pathology, such as interruption of stress granule dynamics (8) and chronic UPR activation (2). The UPR appears to be different in young and aged tau transgenic mice, consistent with a number of other studies showing that the UPR changes with age (9). Moreover, while the UPR can lead to cell death under certain conditions, it is also a necessary cascade that can have protective effects (9). We will evaluate how tau and the aging neuronal environment converge to regulate proteotoxicity through the UPR cascade. Specifically, we will evaluate the specificity of UPR activation by tau in the aging brain. We also will determine whether inhibition of the UPR protects neurons from tau toxicity through the use of AAV vectors encoding the 3 distinct branches of the UPR. Lastly, we will determine the mechanism through which tau inhibits ERAD and triggers the UPR, paying particular attention to the valosin-containing protein (VCP/p97/cdc48)/Hrd1 ERAD complex. By manipulating the UPR experimentally, we will be able to determine whether some aspects of UPR are beneficial and others detrimental for AD progression.