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

项目总结 星形胶质细胞通过调节脑血管反应性在脑血流量调节中发挥关键作用 (CVR)和神经血管偶联(NVC)。CBF在许多神经疾病中调节失调，包括中风 和阿尔茨海默病(AD)，并被认为是导致神经元功能障碍导致痴呆的原因。这个 导致CBF失调的因素仍然没有解决，但对于理解和 开发治疗痴呆症的新干预措施。我们假设缺血损伤会导致持续的终生 星形胶质细胞增多症，从而对脑血流调节和认知能力产生负面影响。从流行病学来看， 很大一部分AD患者存在缺血性损伤，而遭受缺血性损伤的患者更有可能 患上痴呆症。在试点研究中，我们发现暴露在单侧轻度缺血损伤中的小鼠表现出 持续性反应性星形胶质细胞增生症，持续8个月。此外，这一慢性时间点与受损的时间重合 单侧伤害时双侧大脑半球CVR和NVC的反应，与患者的观察结果相似 人口。脑血流量失调会导致持续性低氧，并促进Aβ的产生，进而 收缩血管，加重缺氧。由于大脑对能量的需求很高，但能量储存很少，这种相互作用 在CBF失调和Aβ之间，可能引发能源危机不断升级的恶性循环。初步数据 提示A和缺血对NVC损伤可能具有相加作用。因此， 脑缺血引起的脑血流量失调可能是痴呆病理的触发催化剂。 由于传统上将缺血性卒中和阿尔茨海默病分开，因此对两者之间的相互作用研究还不够深入 学科，将这种关系限制在相关领域，排除因果关系推论。在这个项目中， 我们将轻度缺血模型与以β沉积为特征的转基因AD小鼠模型相结合 全面探讨脑缺血引起的脑血流调节障碍如何与Aβ相互作用并参与 终生认知障碍，重点是星形胶质细胞依赖的血管收缩机制。简单地说， 我们结合遗传学、生理学、药理学和行为学的策略来：(目标1)绘制进程图 在一生中，星形胶质细胞增多症、脑血管再生和神经上皮损伤、认知/行为缺陷和β病理的发生 缺血、Aβ和衰老的交集揭示时间因果关系；(目标2)测试20-HETE的作用，以及 星形胶质细胞衍生的血管收缩信号，在缺血诱导的CBF失调和认知/行为障碍中； 和(目标3)确定代谢性谷氨酸受体5在缺血诱导的反应中是否重新表达 星形胶质细胞驱动20-HETE的合成以损害NVC和CVR。我们的发现将揭示出对 中风和阿尔茨海默病交界处CBF失调的细胞和分子机制。这 可以利用信息来设计新的生物标记物(CVR/NVC损伤)和治疗靶点 用于痴呆症的早期干预(恢复CVR/NVC)。

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.