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

项目摘要/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 (病理性的)缠结形式的tau，并在脑组织的浅层发现选择性神经元丢失。 内嗅皮层和海马区CA1。然而，积累的准确的神经细胞类型 缠结和调节这种选择性神经元脆弱性的生化途径尚不清楚。我们，还有 另一些研究人员发现，海马区EC和CA1区的兴奋性神经元对tau特别敏感 病理学。值得注意的是，Wolfram综合征1(WFS1)是一种定位于内质的跨膜糖蛋白 在这两个区域的兴奋性神经元中有不同的表达。WFS1功能障碍一直是 被发现会导致神经退化以及压力和抑郁，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 观察到，我假设tau病理会减少WFS1的表达，导致ER和 胞浆钙稳态失调、内质网应激途径持续激活及其他 未知的通路，这反过来将加剧tau病理，突触功能障碍，神经元丢失 和认知缺陷。为了验证这一假设，这一提议将(1)确定WFS1的表达是否具有兴奋性 内侧内嗅皮层(MEC)浅层和海马CA1区的神经元是脆弱的 研究tau转基因小鼠和人类AD的tau病理改变；(2)研究WFS1的过表达 改善内质网钙平衡失调、内质网应激、tau病理、胶质细胞激活、突触功能障碍和 RTg4510tau小鼠的认知缺陷；(3)探讨WFS1在大脑中的条件性敲除是否加剧 内质网钙代谢紊乱、内质网应激、tau病理、神经胶质细胞激活、突触功能障碍和认知障碍 在rTg4510tau小鼠中；和(4)确定WFS1和tau之间的相互作用，以及另外的生化途径 导致表达WFS1的兴奋性神经元对tau病理易感性的内质网应激途径 在tau转基因小鼠和人类AD中。确定病理性tau-2的分子机制 AD中介导的神经元易损性和神经变性有助于发现新的药物靶点 可以有针对性地保护脆弱的神经元。此外，还提出了表征细胞的方法 阿尔茨海默病中易受病理性蛋白影响的人群可适用于多种退行性疾病 这也表明了选择性的、细胞的脆弱性。

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.