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

阿尔茨海默病中谷氨酸转运蛋白依赖性神经血管耦合的失调

• 批准号: 10657894
• 负责人: Joshua Goodyear Jackson
• 金额: $ 43.07万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657894
• 关键词: Ablation; Alzheimer' s Disease; Alzheimer' s disease model; Astrocytes; Attenuated; Basal metabolic rate; Bioenergetics; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain region; Buffers; Cerebrovascular Circulation; Development; Diameter; Disease; Elements; Endothelial Cells; Excision; Gene Expression; Genetic; Glucose; Glutamate Transporter; Glutamates; Glycogen; Goals; Impaired cognition; Impairment; Kinetics; Knowledge; Link; Location; Measures; Mediating; Membrane; Metabolic; Methods; Microscopy; Mitochondria; Neurodegenerative Disorders; Neurons; Pathology; Pathway interactions; Pericytes; Positioning Attribute; Process; Protein Isoforms; Proteomics; Regulation; Role; Shapes; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Somatosensory Cortex; Stimulus; Symptoms; Synapses; Synaptic Cleft; Testing; Trees; Vascular Smooth Muscle; Vasodilation; arteriole; brain metabolism; cell type; constriction; cost; glucose metabolism; human disease; in vivo; in vivo imaging; mitochondrial dysfunction; mouse model; neural; neurovascular; neurovascular coupling; neurovascular unit; operation; pharmacologic; response; transcriptomics; two-photon; vasoconstriction

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.

阿尔茨海默氏病中谷氨酸转运蛋白依赖性神经血管耦合的失调 脑血流，葡萄糖代谢和神经血管耦合损害的减少是 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 并可能在或加重疾病之前。这些定义也伴随着谷氨酸的损失 转运蛋白Na+/Ca2+交换器（NCX）同工型，并在线粒体动力学和 在过去的几年中，我们证明了星形胶质细胞GLU转运蛋白夫妇 通过Na+/Ca2+交换（NCX）的反转操作，细胞内Ca2+的增加。我们证明了 线粒体在星形胶质细胞过程中与GLU转运蛋白共同构图，并且 线粒体定位相对于GLU转运蛋白和突触取决于Ca2+，并且 线粒体形状Ca2+信号。此外，我们发现谷氨酸运输足以唤起 反向NCX下游的动脉直径（转运蛋白依赖性NVC）的增加。这些和 其他观察结果提出了中心假设，即GLU运输和反转Na+/Ca2+ 交换形成了由线粒体调节的星形胶质细胞中的功能信号通路， 该途径的过度激活有助于在AD发展过程中观察到的病理学。 生物能学。 AIM 1确定如果在AD中受到转运蛋白介导的NVC的损害。在AIM 2中，我们将确定是否更改 AD的星形细胞线粒体分布效应。使用体内成像或皮质血流， 谷氨酸转运蛋白的局部应用以及选择性操纵（遗传和药理） 下游信号传导和线粒体动力学，我们将剖析谷氨酸之间的关系 在控制皮质血流中的运输，NCX和线粒体，并确定是否丢失 信号轴影响AD中的血流调节/神经血管耦合。