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的进展和 阿尔茨海默病的发病机制既来自神经元内部，也来自神经元之间 类普里子传播。然而，导致这些致病过程的机制 目前仍不清楚。在这里，我们将通过利用已知的反聚集剂来填补我们知识中的这些空白 可以在神经元内外发挥作用的小分子伴侣，可以明显地调节tau 装配和可能的毒性。事实上，这些小的热休克蛋白已知存在于 细胞外间隙，并与tau缠结和淀粉样β(A？)斑块相关。我们也 要知道，在老化的大脑中，小的热休克蛋白会增加，甚至在阿尔茨海默氏症的大脑中会增加。我们的 研究小组发现，在体内，一种小的热休克蛋白可以阻止tau聚集，降低tau水平 并在tau转基因小鼠模型中恢复海马区功能；但磷酸化的 活性受损的变体实际上可能会产生更多的tau寡聚体，从而增加毒性。 我们现在有证据表明，其他小的热休克蛋白也可以防止tau聚集，甚至 这两个小热休克蛋白的小肽核心都能阻止tau聚集。使用 这些工具，我们现在可以测试的假设，即牛磺酸毒性产生的结构变化 由可以在神经元内外发挥作用的小热休克蛋白引起的tau组装。 为了测试这一点，我们将确定不同的热休克蛋白小变体对tau寡聚体形成的影响。 和领悟。我们还将确定细胞内小分子热休克蛋白对功能缺陷的影响。 在tau蛋白毒性的小鼠模型中。我们将确定细胞外小分子的影响 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摄取的影响。 通过这些研究，我们预计我们将找到调节tau聚集的方法，使用 小的热休克蛋白，这将使我们能够深入了解有毒tau中间体的结构。我们也会 确定不同的小HSP变异体是否可以从内部区分异常tau 在大脑中的神经元之外，可能允许我们提高 针对这一机制的治疗。

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.