Dysregulation of glutamate transporter-dependent neurovascular coupling in Alzheimer's disease

阿尔茨海默病中谷氨酸转运体依赖的神经血管耦联失调 脑血流量减少，葡萄糖代谢和神经血管耦合受损， 与许多神经退行性疾病和认知能力下降有关，包括阿尔茨海默氏症 疾病 并且可能先于或加重疾病。这些赤字也伴随着谷氨酸的损失 转运蛋白，Na+/Ca 2+交换器（NCX）亚型，以及线粒体动力学和 在过去的几年里，我们已经证明星形胶质细胞Glu转运蛋白与 通过Na+/Ca 2+交换（NCX）的反向操作增加细胞内Ca 2+。我们证明 在星形胶质细胞过程中，线粒体与Glu转运蛋白共区室化， 线粒体相对于Glu转运蛋白和突触的定位依赖于Ca 2+， 线粒体形成Ca 2+信号。此外，我们发现谷氨酸转运足以引起 逆转NCX下游的小动脉直径增加（转运蛋白依赖性NVC）。这些和 其他观察结果提示了一个中心假设，即Glu转运和逆转Na+/Ca 2 + 交换在星形胶质细胞中形成由线粒体调节的功能性信号通路， 该途径的过度激活导致AD发展过程中观察到的病理学。在 生物能量学 目的1确定AD患者转运蛋白介导的NVC是否受损。在目标2中，我们将确定是否改变 AD对星形胶质细胞线粒体分布功能的影响。使用体内成像或皮质血流， 谷氨酸转运蛋白的局部应用和选择性操作（遗传和药理学） 下游信号和线粒体动力学，我们将剖析谷氨酸之间的关系， 运输，NCX和线粒体在控制皮质血流，并确定如果失去这一点， 信号传导轴影响AD中的血流调节/神经血管偶联。

Dysregulation of glutamate transporter-dependent neurovascular coupling in Alzheimer’s disease Decreases in cerebral blood flow, glucose metabolism, and impairment of neurovascular coupling are associated with a number of neurodegenerative disease and cognitive decline, including Alzheimer’s disease and may precede or exacerbate disease. These deficits are also accompanied by loss of glutamate transporters, Na+/Ca2+ exchanger (NCX) isoforms, and deficits in mitochondrial dynamics and Over the last few years, we have demonstrated that astrocytic Glu transporters couple to increases in intracellular Ca2+ through reversed operation of Na+/Ca2+ exchange (NCX). We demonstrated that mitochondria co-compartmentalize with Glu transporters in astrocyte processes and that mitochondrial positioning relative to Glu transporters and synapses is dependent upon Ca2+ and that mitochondria shape Ca2+ signal. Moreover, we found that glutamate transport is sufficient to evoke increases in arteriole diameter (transporter-dependent NVC) downstream of reversed NCX. These and other observations have prompted the central hypothesis that Glu transport and reversed Na+/Ca2+ exchange form a functional signaling pathway in astrocytes that is modulated by mitochondria and that excessive activation of this pathway contributes to pathology observed during the development of AD. In bioenergetics. Aim 1Determine if transporter-mediated NVC is impaired in AD. In Aim 2, we will determine if altered astrocytic mitochondria distribution function effects of AD. Using in vivo imaging or cortical blood flow, local application of glutamate transporters, and selective manipulation (genetic and pharmacologic) of downstream signaling and mitochondrial dynamics, we will dissect the relationship between glutamate transport, NCX, and mitochondria in the control of cortical blood flow and determine if loss of this signaling axis impacts blood flow regulation/neurovascular coupling in AD.