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.

项目概要 星形胶质细胞通过调节脑血管反应性在脑血流（CBF）调节中发挥关键作用 (CVR) 和神经血管耦合 (NVC) 在许多神经系统疾病中失调，包括中风。 和阿尔茨海默病（AD），并且被认为会导致神经元功能障碍，从而导致痴呆。 导致 CBF 失调的因素仍未解决，但对于理解其病理学至关重要，并且 开发新的干预措施来治疗痴呆症，我们勇敢地说，缺血性损伤会导致持续的终生痴呆。 星形胶质细胞增多症，对 CBF 调节和认知能力产生负面影响。 很大一部分AD患者存在缺血性损伤，并且遭受缺血性损伤的患者更有可能 在初步研究中，我们发现暴露于单侧轻度缺血性损伤的小鼠表现出痴呆。 此外，持续性反应性星形胶质细胞增生症持续长达 8 个月，这一慢性时间点与受损时间点一致。 尽管受到单侧损伤，两个半球的 CVR 和 NVC 反应，模仿了患者的观察结果 CBF 失调会导致持续缺氧并促进 Aβ 的产生，进而导致 Aβ 的产生。 由于大脑的能量需求很高，但能量储存却很少，因此这种相互作用会导致血管收缩和缺氧加剧。 初步数据显示，CBF 失调和 Aβ 之间的相互作用可能会引发能源危机的恶性循环。 这表明 A 和缺血可能对 NVC 损伤有累加效应，支持这一观点。 缺血引起的 CBF 失调可能是痴呆病理学的触发催化剂。 由于传统上将两者分开，因此对缺血性中风和 AD 之间的相互作用尚未进行充分研究 学科，将这种关系限制在相关领域并排除因果关系推论。 我们将轻度缺血模型与以 Aβ 沉积为特征的转基因 AD 小鼠模型相结合， 全面探究缺血引起的 CBF 失调如何与 Aβ 相互作用并有助于 整个生命周期的认知障碍，重点是星形胶质细胞依赖性血管收缩机制。 我们整合遗传、生理、药理学和行为策略来：（目标 1）绘制进展图 星形胶质细胞增生、CVR 和 NVC 损伤、认知/行为缺陷以及整个生命周期的 Aβ 病理学 缺血、Aβ 和衰老的交叉点揭示时间因果关系（目标 2）测试 20-HETE 的作用； 星形胶质细胞衍生的血管收缩信号，在缺血引起的 CBF 失调和认知/行为缺陷中； （目标 3）确定代谢型谷氨酸受体 5 是否在缺血诱导的反应中重新表达 星形胶质细胞驱动 20-HETE 合成以损害 NVC 和 CVR，我们的研究结果将揭示对这一现象的新见解。 中风和 AD 交叉点 CBF 失调的细胞和分子机制。 可以利用信息来设计新的生物标志物（CVR/NVC 损伤）和治疗靶点 用于痴呆症的早期干预（恢复 CVR/NVC）。