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.

阿尔茨海默病中谷氨酸转运体依赖性神经血管偶联的失调