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.

项目总结