The contribution of Ly6h to Alzheimers Disease

摘要 尽管人们的兴趣主要集中在淀粉样β蛋白和磷酸化tau在 阿尔茨海默病(AD)的发病机制是一种早期和持久的假说属性 胆碱能信号丧失的认知障碍。我们最近证明了所有这些 元素之间通过Ly6h联系在一起，Ly6h是一种内源性的钙渗透α7尼古丁抑制物 乙酰胆碱受体(NAChRs)。我们发现，淀粉样β蛋白会降低Ly6h，导致 增加α7 nAChRs的组装，从而将基础胆碱能转化为神经毒性 发信号。重要的是，我们还发现在颞叶皮质和脑脊液中Ly6h的水平 与AD患者的病情严重程度呈负相关。目前的建议旨在 在AD动物模型中，用相关数据来补充这些发现。特别是，我们将 确定慢病毒敲除海马区Ly6h加重AD的程度 推动α7 nAChRs和磷酸化tau的增加。将预期的细胞效应关联起来 随着海马体依赖行为的改变，我们也将测试表现的恶化 在Y迷宫、Morris水迷宫和新的物体识别实验中。我们还将表演 对阿尔茨海默病模型小鼠神经元的药理实验以扩展我们的体外结果，这 提示Ly6h和Alpha7 nAChRs相互调节，淀粉样β蛋白 需要字母7的开放构象来驱动这一过程。最后，我们将关联Ly6h水平 在脑脊液和外体中有疾病严重程度的个别患者，我们会迅速发展成 酶联免疫吸附试验，允许更常规地进行相关测量。结果来自 因此，我们提案中的实验将提供关于Ly6h如何在 在分子、细胞和行为水平上参与AD的发病。同时我们的 实验还将提供有价值的临床数据和可能有助于早期诊断的新工具 公元一代的。

Abstract Although interest has focused on crucial roles for amyloid beta and phosphorylated tau in pathogenesis of Alzheimer's disease (AD), an earlier and persistent hypothesis attributes cognitive impairment to loss of cholinergic signaling. We recently demonstrated that all these elements are linked by Ly6h, an endogenous inhibitor of Ca2+-permeable alpha7 nicotinic acetylcholine receptors (nAChRs). We found that amyloid beta reduces Ly6h, resulting in increased assembly of alpha7 nAChRs and thus a conversion of basal cholinergic to neurotoxic signaling. Importantly, we also found that Ly6h levels in temporal cortex and cerebrospinal fluid are inversely correlated with disease severity in AD patients. The present proposal seeks to complement these findings with related data in an animal model of AD. In particular, we will determine the degree to which lentiviral knockdown of Ly6h in the hippocampus exacerbates AD- driven increases in alpha7 nAChRs and phosphorylated tau. To correlate expected cellular effects with changes in hippocampal-dependent behaviors, we will also test for worsening of performance in Y-maze, Morris water maze and novel object recognition assays. We will also perform pharmacological experiments on neurons from AD model mice to extend our in vitro results, which suggest that Ly6h and alpha7 nAChRs reciprocally regulate each other, and that amyloid beta requires the open conformation of alpha7 to drive this process. Lastly, we will correlate Ly6h levels in CSF and exosomes with disease severity in individual patients, and we will develop a rapid ELISA assay to allow for related measurements to be made more routinely. Results from experiments in our proposal will thus provide an integrated overview about how Ly6h functions at a molecular, cellular and behavioral level to contribute to AD pathogenesis. At the same time our experiments will also provide valuable clinical data and a new tool that may aid in earlier diagnosis of AD.