Stroke Disordered Breathing and its Impact on Cognitive Decline in Aging, Alzheimer's Disease and Cerebral Amyloid Angiopathy

中风呼吸障碍及其对衰老认知能力下降、阿尔茨海默病和脑淀粉样血管病的影响

• 批准号: 10157596
• 负责人: Jun Li
• 金额: $ 413.77万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10157596
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Animal Model; Animals; Apnea; Area; Astrocytes; Blood Vessels; Brain; Brain Stem; Breathing; Cell Nucleus; Cerebral Amyloid Angiopathy; Cerebrum; Chemoreceptors; Cognition; Cognitive; Cognitive deficits; Complement Factor B; Data; Development; Disease; Disease Progression; Frequencies; Functional disorder; Gliosis; Impaired cognition; Impairment; Incidence; Individual; Infarction; Injections; Intervention; Ischemic Stroke; Link; Mediating; Mediator of activation protein; Middle Cerebral Artery Occlusion; Modeling; Molecular; Motor; Mus; Nerve Degeneration; Outcome; Pathology; Patients; Periodicity; Peripheral; Pharmacology; Phenotype; Physiological; Physiology; Prevalence; Recovery; Regulation; Respiration; Respiration Disorders; Secondary to; Serum; Severities; Sex Differences; Signal Transduction; Source; Stroke; Survivors; Tg2576; Therapeutic; Tidal Volume; Time; Transforming Growth Factor beta; Transforming Growth Factors; Transgenic Mice; Treatment Efficacy; United States; Vascular Diseases; Work; age related; aged; amyloid pathology; astrogliosis; cognitive function; cognitive recovery; disability; human old age (65+); improved; infancy; inhibitor/antagonist; knock-down; mortality; motor deficit; mouse model; neurovascular; normal aging; post stroke; receptor; respiratory; sex; stroke incidence; stroke model; stroke patient; stroke therapy; therapy design; ventilation; β-amyloid burden

PROJECT SUMMARY Stroke is the leading cause of long-term disability in the United States. The major contributors to stroke-related disability are motor and cognitive deficits, which tend to worsen over time, especially in aged individuals. Stroke also accelerates other age-related diseases, such as Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA). The prevalence of respiratory dysfunction is high in stroke patients and it impairs recovery and increases mortality. Studies investigating the mechanisms underlying stroke-induced respiratory dysfunction (SIRD) are in their infancy. Even less is known about how disordered breathing can influence motor and cognitive outcomes after stroke, especially in aged individuals that have other features of neurodegeneration, including cerebral amyloid. There are currently no animal models of post-stroke respiratory dysfunction, limiting our ability to investigate the mechanism of respiratory dysfunction after stroke or to develop interventions to stabilize breathing to improve cognition. Our preliminary data shows that stroke leads to the development of periodic breathing and apnea in mice, the severity of which is correlated with both mortality and progressive cognitive decline in survivors. Stroke is also very common in AD and CAA patients and SIRD may contribute to cognitive decline in AD and CAA, increasing amyloid burden. Treatment of stroke disordered breathing may decrease Aβ burden and reduce neurodegeneration and cognitive decline in AD and CAA patients with vascular disease. We have recently discovered that stroke induces astrogliosis in brain areas remote from the infarct, including chemoreceptor areas of the brainstem and reducing gliosis specifically in brainstem improves SIRD and cognition. Mechanistically, we will determine the cellular source (likely astrocytes at the neurovascular interface), the molecular mediators (likely transforming growth factor β, TGFβ), and the physiological contribution of this to the development and progression of SIRD and cognitive decline. We have developed an animal model of post- stroke respiratory dysfunction that recapitulates the physiology seen in stroke patients and is tightly linked to post-stroke cognitive function. We will now investigate sex differences in this model and investigate if stroke accelerates cognitive decline in transgenic mice that develop AD or CAA. Finally we will determine the mechanisms responsible for stroke-induced respiratory pathophysiology and will attempt to develop therapeutic approaches to stabilize breathing and enhance recovery of cognitive function. Our central hypothesis is that the severity of disordered breathing correlates with cognitive and motor decline after stroke in wild-type, AD and CAA mice and that this is secondary to widespread age-enhanced astrogliosis, leading to impaired chemoreception and progressive apnea. The proposed work will determine how stroke affects control of breathing in “normal” aging, in AD and in CAA, and whether treatments designed to improve this respiratory phenotype reduce disease progression.

项目摘要 中风是美国长期残疾的主要原因。与中风有关的主要贡献者 残疾是运动和认知缺陷，随着时间的流逝往往会恶化，尤其是在老年人中。中风 还加速了其他与年龄有关的疾病，例如阿尔茨海默氏病（AD）和脑淀粉样血管病 （CAA）。中风患者的呼吸功能障碍的患病率很高，它会损害康复并增加 死亡。研究了研究中风引起的呼吸功能障碍（SIRD）的机制 他们的婴儿期。关于呼吸无序会影响运动和认知结果的知之甚少 中风后，特别是在具有其他神经退行性特征的老年人中，包括大脑 淀粉样蛋白。目前尚无中风后呼吸功能障碍的动物模型，限制了我们的能力 研究中风后呼吸障碍的机制或制定干预措施以稳定呼吸 改善认知。我们的初步数据表明，中风会导致定期呼吸和 小鼠的呼吸暂停，其严重程度与死亡率和进行性认知降低相关 幸存者。中风在AD和CAA患者中也很常见，SIRD可能导致认知能力下降 AD和CAA，增加淀粉样蛋白伯嫩。中风无序呼吸的治疗可能会降低Aβ伯嫩 并减少AD和CAA血管疾病患者的神经变性和认知下降。我们有 最近发现，中风会引起远离梗塞的大脑区域的星形脂肪症，包括 脑干的化学感受器区域并在脑干上特别降低神经胶质病可改善SIRD和 认识。从机械上讲，我们将确定细胞源（可能在神经血管界面处的星形胶质细胞）， 分子介体（可能转化生长因子β，TGFβ），并且它的身体贡献 SIRD和认知能力下降的发展和发展。我们已经开发了一种动物模型。 中风呼吸道功能障碍概括了中风患者的生理学，并与 冲程后认知功能。现在，我们将调查该模型中的性别差异，并研究中风是否 加速发展AD或CAA的转基因小鼠的认知能力下降。最后，我们将确定 负责中风引起的呼吸病理生理学的机制，并将尝试开发治疗 稳定呼吸并增强认知功能恢复的方法。我们的核心假设是 呼吸无序的严重程度与野生型，AD和中风后的认知和运动下降相关 CAA小鼠，这是宽度宽度增强的星形胶质细胞增多的继发性，导致受损 化学感受和进行性呼吸暂停。拟议的工作将决定中风如何影响对 在“正常”衰老，AD和CAA中呼吸，以及旨在改善这种呼吸系统的治疗方法 表型降低了疾病的进展。