Hsp70_DNAJ interface as a drug target for Alzheimers disease and TBI

微管相关蛋白tau现在被认为有助于疾病进展， 阿尔茨海默病的发病机制，无论是从神经元内，甚至神经元之间， 朊病毒样传播然而，导致这些致病过程的机制 仍然不清楚。在这里，我们将通过利用已知的抗聚集剂来填补我们知识中的这些空白。 可以在神经元内部和外部发挥作用以明显调节tau蛋白的小分子伴侣 组装和可能的毒性。事实上，已知这些小的热休克蛋白存在于 细胞外间隙，并与tau缠结和淀粉样蛋白（AAPs）斑块相关。我们也 我们知道小Hsps在衰老的大脑中增加，甚至在阿尔茨海默氏症的大脑中增加。我们 研究小组表明，一种小的热休克蛋白阻止tau蛋白聚集，降低体内tau蛋白水平 并在tau转基因小鼠模型中恢复海马功能;但磷酸化的 具有受损活性的变体实际上可能通过产生更多的tau寡聚体而促进毒性。 我们现在有证据表明，其他小Hsps也可以阻止tau蛋白聚集，甚至 只有这两种小HSP的小肽核心能够阻断tau聚集。与 这些工具，我们现在可以测试的假设，tau毒性产生由于结构变化， 由小的Hsps引起的tau组装，可以在神经元内外发挥作用。 为了验证这一点，我们将确定不同的小Hsp变体对tau寡聚体形成的影响。 和摄取。我们还将确定细胞内小Hsps对功能缺陷的影响， 在tau蛋白毒性的小鼠模型中。我们将确定细胞外小分子 热休克蛋白对小鼠和人类tau蛋白毒性模型中功能缺陷和tau蛋白摄取的影响。 通过这些研究，我们预计我们将确定使用以下方法调节tau聚集的方法： 小的热休克蛋白，这将使我们能够找到有毒的tau中间体的结构。我们也将 确定不同的小Hsp变异体是否可以从内部对异常tau进行差异分类 在大脑的神经元之外，这可能使我们能够提高 针对这种机制的治疗方法。

The microtubule-associated protein tau is now thought to contribute to disease progression and pathogenesis in Alzheimer’s disease both from within neurons and even between neurons via prion-like propagation. However, mechanisms that contribute to these pathogenic processes remain unclear. Here, we will fill these gaps in our knowledge by exploiting known anti-aggregant small chaperones that can function both inside and outside of neurons to distinctly regulate tau assembly and possibly toxicity. In fact, these small heat shock proteins are known to reside in the extracellular space and associate with both tau tangles and amyloid ß (Aß) plaques. We also know that small Hsps increase in the aging brain and even further in the Alzheimer’s brain. Our team showed that a small heat shock protein blocks tau aggregation, reduces tau levels in vivo and restores hippocampal function in a tau transgenic mouse model; but a phosphorylated variant that has impaired activity may actually promote toxicity by producing more tau oligomers. We now have evidence that the other small Hsps can also prevent tau aggregation, and even just small peptidic cores of both these small Hsps are capable of blocking tau aggregation. With these tools, we can now test the hypothesis that tau toxicity arises due to structural changes in tau assemblies brought on by small Hsps that can function both inside and outside of the neuron. To test this, we will determine the impact of distinct small Hsp variants on tau oligomer formation and uptake. We will also determine the impact of intracellular small Hsps on functional deficits in a mouse model of tau proteotoxicity. And we will determine the impact of extracellular small Hsps on functional deficits and tau uptake in mouse and human models of tau proteotoxicity. Through these studies, we anticipate that we will identify ways to regulate tau aggregation using small Hsps, which will allow us to home in on structures of toxic tau intermediates. We also will determine whether distinct small Hsp variants can differentially triage aberrant tau from inside and outside of the neuron in the brain, possibly allowing us to improve the specificity of therapeutics targeting this mechanism.