Astrocyte regulation of cerebral blood flow at the intersection of ischemia and Alzheimer's disease

星形胶质细胞对缺血和阿尔茨海默病交叉点脑血流的调节

• 批准号: 10774128
• 负责人: Anusha Mishra
• 金额: $ 68.61万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-22 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10774128
• 关键词: AD transgenic mice; Abeta synthesis; Ablation; Acute; Adult; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid beta-Protein; Amyloidosis; Architecture; Astrocytes; Attenuated; Autopsy; Behavior; Behavioral; Bilateral; Biological Assay; Biological Markers; Blood capillaries; Blood flow; Brain; Cerebrovascular Circulation; Cerebrovascular system; Chronic; Cognitive; Coupled; Data; Dementia; Development; Discipline; Disease; Early Intervention; Epidemiology; Etiology; Evaluation; Exposure to; Functional disorder; Future; Genetic; Health; Human; Hydroxyeicosatetraenoic Acids; Hypoxia; Immunohistochemistry; Impaired cognition; Impairment; Infarction; Intervention; Ischemia; Ischemic Stroke; Lesion; Link; Longevity; Measurement; Metabolic; Mixed Function Oxygenases; Modeling; Molecular; Monitor; Mus; Nerve Degeneration; Nervous System Physiology; Neuronal Dysfunction; Outcome; Pathogenesis; Pathology; Patients; Peptide Initiation Factors; Physiological; Pilot Projects; Play; Procedures; Process; Regulation; Reporting; Rodent; Role; Signal Transduction; Slice; Stroke; Testing; Tg2576; Therapeutic Intervention; Time; Tissues; Trees; Vascular blood supply; Vasoconstrictor Agents; abeta accumulation; abeta deposition; arteriole; astrogliosis; beta amyloid pathology; brain cell; catalyst; cerebrovascular; cognitive performance; comorbidity; constriction; design; emerging adult; experimental study; human old age (65+); hypoperfusion; improved; in vivo; insight; ischemic injury; metabotropic glutamate receptor 5; mind control; mouse model; nervous system disorder; neural; neurovascular; neurovascular coupling; novel; patient population; pharmacologic; preservation; prevent; receptor; response; subcortical ischemic vascular disease; therapeutic target; treatment strategy

PROJECT SUMMARY Astrocytes play a key role in cerebral blood flow (CBF) regulation by modulating cerebrovascular reactivity (CVR) and neurovascular coupling (NVC). CBF is dysregulated in many neurological disorders, including stroke and Alzheimer’s disease (AD), and is proposed to contribute to neuronal dysfunction leading to dementia. The factors that drive CBF dysregulation remain unresolved but are critical to understanding the pathobiology of, and developing novel interventions for, dementia. We hypothesize that ischemic injuries induce persistent life-long astrogliosis, with a consequent negative impact on CBF regulation and cognitive performance. Epidemiologically, a large fraction of AD patients harbor ischemic injuries, and patients who suffer ischemic injuries are more likely to develop dementia. In pilot studies, we find that mice exposed to a unilateral mild ischemic injury demonstrate persistent reactive astrogliosis lasting up to 8 months. Further, this chronic time point coincides with impaired CVR and NVC response in both hemispheres despite the unilateral insult, mimicking observations in patient populations. CBF dysregulation would produce persistent hypoxia and facilitate Aβ production, which, in turn, can constrict vessels and worsen hypoxia. As the brain has a high energy demand but few energy stores, this interplay between CBF dysregulation and Aβ can initiate a vicious escalating cycle of energy crisis. Preliminary data suggesting that A and ischemia may have additive effects on NVC impairment support this concept. Thus, ischemia-induced CBF dysregulation could be a triggering catalyst in dementia pathology. Interactions between ischemic stroke and AD are understudied because of traditional separation of the two disciplines, confining this relationship to the correlative realm and precluding causality inferences. In this project, we combine a model of mild ischemia with a transgenic AD mouse model featuring Aβ deposition to comprehensively interrogate how ischemia-induced CBF dysregulation interacts with Aβ and contributes to cognitive impairment across life span, with a focus on astrocyte-dependent vasoconstrictive mechanisms. Briefly, we integrate genetic, physiological, pharmacological, and behavioral strategies to: (Aim 1) chart the progression of astrogliosis, CVR and NVC impairments, cognitive/behavior deficits, and Aβ pathology across life span at the intersection of ischemia, Aβ, and aging to unveil temporal causality links; (Aim 2) test the role of 20-HETE, an astrocyte-derived vasoconstrictive signal, in ischemia-induced CBF dysregulation and cognitive/behavior deficits; and (Aim 3) determine whether re-expression of metabotropic glutamate receptor 5 in ischemic-induced reactive astrocytes drives 20-HETE synthesis to impair NVC and CVR. Our findings will reveal novel insights into the cellular and molecular mechanisms that underlie CBF dysregulation at the intersection of stroke and AD. This information could be leveraged to design both new biomarkers (CVR/NVC impairment) and therapeutic targets for early interventions (restoring CVR/NVC) for dementia.

项目总结