Investigating the vulnerability of WFS1-expressing excitatory neurons to tau pathology in early Alzheimer's disease.

项目总结/摘要 在阿尔茨海默病（AD）的早期阶段，过度磷酸化和构象异常 已经在神经元的浅层中发现了缠结形式的（病理性）tau蛋白和选择性神经元损失。 内嗅皮层和海马CA 1区。然而，累积的精确神经元细胞类型 缠结和介导这种选择性神经元脆弱性的生物化学途径尚不清楚。我们也这么想 其他人发现，海马EC和CA 1区的兴奋性神经元特别容易受到tau蛋白的影响。 病理值得注意的是，Wolfram综合征1（WFS 1），一种定位于内质网的跨膜糖蛋白， 内质网（ER）在这两个区域的兴奋性神经元中差异表达。WFS 1功能障碍 发现有助于神经变性以及压力和抑郁症，可能是通过调节 内质网（ER）应激和/或下丘脑-垂体-肾上腺（HPA）轴。基于这些 根据这些观察，我假设tau蛋白病理学将减少WFS 1的表达，导致ER， 胞浆钙稳态失调，持续激活ER应激途径和其他迄今为止 未知的途径，这反过来又会加剧tau病理学，突触功能障碍，神经元损失 和认知缺陷为了检验这一假设，该提议将（1）确定表达WFS 1的兴奋性神经元是否是神经元的一部分。 内侧内嗅皮层（MEC）浅层和海马CA 1区的神经元易受损伤 （2）研究在tau转基因小鼠和人AD中， 改善ER钙稳态失调、ER应激、tau病理学、神经胶质活化、突触功能障碍和 rTg 4510 tau小鼠中的认知缺陷;（3）探索脑中WFS 1的条件性敲除是否加剧 ER钙稳态异常、ER应激、tau病理学、神经胶质活化、突触功能障碍和认知缺陷 在rTg 4510 tau小鼠中;和（4）定义WFS 1和tau之间的相互作用，以及另外的生化途径 ER应激通路是表达WFS 1的兴奋性神经元对tau病理的脆弱性的基础 在tau转基因小鼠和人AD中。确定病理性tau蛋白的分子机制- 介导的神经元脆弱性和神经退行性变的AD可能有助于发现新的药物靶点 可以用来保护脆弱的神经元此外，提出了表征细胞的方法， 易受AD中病理蛋白影响的人群可应用于广泛的退行性疾病 也显示出选择性的细胞脆弱性。

Project Summary/Abstract In the earliest stages of Alzheimer’s disease (AD), hyperphosphorylated and conformationally abnormal (pathological) tau in the form of tangles, and selective neuronal loss have been found in the superficial layers of the entorhinal cortex and in the CA1 of hippocampus. However, the precise neuronal cell types that accumulate tangles and the biochemical pathways mediating this selective neuronal vulnerability are not known. We, and others, have found that excitatory neurons in the EC and CA1 of hippocampus are particularly vulnerable to tau pathology. Notably, Wolfram Syndrome 1 (WFS1), a transmembrane glycoprotein localized to the endoplasmic reticulum (ER), is differentially expressed in excitatory neurons in those two regions. WFS1 dysfunction has been found to contribute to neurodegeneration as well as stress and depression, possibly by regulating the endoplasmic reticulum (ER) stress and/or the hypothalamic–pituitary–adrenal (HPA) axis. Based on these observations, I hypothesize that tau pathology will reduce the expression of WFS1, resulting in ER and cytosolic calcium dyshomeostasis, persistent activation of ER stress pathways and other as yet unknown pathways, which in turn will exacerbate tau pathology, synaptic dysfunction, neuronal loss and cognitive deficits. To test this hypothesis, this proposal will (1) determine if WFS1-expressing excitatory neurons in the superficial layers of medial entorhinal cortex (MEC) and in the CA1 of hippocampus are vulnerable to tau pathology in tau transgenic mice and in human AD; (2) investigate whether overexpression of WFS1 ameliorates ER calcium dyshomeostasis, ER stress, tau pathology, glial activation, synaptic dysfunction and cognitive deficits in rTg4510 tau mice; (3) explore whether conditional knockout of WFS1 in the brain exacerbates ER calcium dyshomeostasis, ER stress, tau pathology, glial activation, synaptic dysfunction and cognitive deficits in rTg4510 tau mice; and (4) define the interaction between WFS1 and tau, and biochemical pathways in addition to the ER stress pathways that underlie the vulnerability of WFS1-expressing excitatory neurons to tau pathology in tau transgenic mice and in human AD. Identifying the molecular mechanisms underlying pathological tau- mediated neuronal vulnerability and neurodegeneration in AD could aid in the discovery of novel drug targets that can be targeted to protect vulnerable neurons. In addition, the approaches proposed to characterize cell populations vulnerable to pathological proteins in AD can be applied to a wide range of degenerative diseases that also show selective, cellular vulnerability.