Impact of Prenatal alcohol on Alzheimer's disease related pathology and cognitive impairment

产前酒精对阿尔茨海默病相关病理和认知障碍的影响

• 批准号: 10387300
• 负责人: Rajesh C Miranda
• 金额: $ 21.41万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387300
• 关键词: Acute; Address; Adult; Affect; Age; Age-Months; Aging; Alcohol abuse; Alcoholism; Alcohols; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; American; Anatomy; Animal Model; Appearance; Area; Astrocytosis; Behavior; Behavioral; Behavioral Assay; Biological; Biological Assay; Blood Vessels; Blood flow; Brain; Cardiovascular Diseases; Cardiovascular system; Caring; Cephalic; Cerebrovascular Disorders; Chronic; Cognitive deficits; Collaborations; Data; Dementia; Disease; Disease susceptibility; Encephalitis; Exhibits; Exons; Exposure to; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; First Pregnancy Trimester; Foundations; Functional disorder; Future; Goals; Health; Heart Hypertrophy; Histologic; Human; Human Amyloid Precursor Protein; Hypertension; Impaired cognition; Impairment; Individual; Inflammation; Institutes; Intervention; Kidney Failure; Knowledge; Lesion; Life; Life Experience; Link; Longevity; Maternal Exposure; Measures; Mental Depression; Metabolic; Metabolic Diseases; Mission; Modeling; Mus; Mutation; Nerve Degeneration; Neurocognitive Deficit; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic; Non-Insulin-Dependent Diabetes Mellitus; Outcome Study; Pathogenicity; Pathology; Persons; Phenotype; Predisposition; Premature Mortality; Premature aging syndrome; Rattus; Recording of previous events; Recovery of Function; Reporting; Research Personnel; Risk; Risk Factors; Rodent; Rodent Model; Senile Plaques; Social Interaction; Swedish mutation; Teenagers; Testing; Transgenes; Transgenic Organisms; Ultrasonography; age related; alcohol prevention; alcohol related consequences; behavioral impairment; cerebrovascular; clinical care; cognitive function; dementia risk; depressive symptoms; disability; disorder risk; early life adversity; early onset; experience; familial Alzheimer disease; fetal; hypertensive; hypoperfusion; innovation; ischemic injury; male; middle age; mouse model; neurobehavioral; novel; object recognition; offspring; prenatal; presenilin-1; social; trend; vapor; virtual; young adult

Project Summary: Persons with fetal alcohol spectrum disorders (FASD) experience life-long neurocognitive deficits as well as social and adaptive dysfunction, but we know virtually nothing about their health as they age. We recently reported that prenatal alcohol-exposure (PAE) resulted in long-term alteration in cranially-directed blood flow and reduced recovery of function after an acute ischemic injury in adulthood. This suggests that PAE is an important risk factor for cerebrovascular diseases and consequently, for dementia and Alzheimer's disease (AD). Young PAE rats also exhibit cognitive deficits and importantly, increased depression-related behaviors which are early predictors of AD. Therefore, in these studies, we will utilize the transgenic TgF344-AD rat which develops AD pathology in aging, to test the hypothesis that PAE will accelerate cerebro-vascular impairment, behavioral dysfunction and the accumulation of AD-related brain lesions, leading to premature aging. Moreover, we will specifically test whether male and female PAE offspring differ in their accumulation of AD-related anatomical and neurobehavioral pathology. We will implement a vapor-chamber model of repeated PAE, to achieve consistent binge-like maternal exposure episodes, spanning the fetal neurogenic period. PAE and control offspring will be assessed from young adults to 15 months of age, by ultrasound imaging of cranially directed blood flow, by a panel of behavioral assays for cognitive dysfunction and depression-like phenotypes, as well as a panel of histological assays for AD pathology. The investigators have a history of collaboration and application of experimental rigor in their areas of complementary expertise in models of aging and PAE, which supports the feasibility of the proposed studies. These studies are significant because they address a critical knowledge gap about the link between early life adversity, i.e., PAE, and the onset of AD. We expect that, if these studies do link PAE to accelerated AD pathology, they will help redefine FASD as a disorder of premature aging and strengthen the premise for investigating mechanisms that link PAE to aging, as well as interventions that decouple this linkage.

项目总结： 患有胎儿酒精谱系障碍(FASD)的人会经历终生的神经认知缺陷以及 社交和适应性障碍，但随着年龄的增长，我们几乎对他们的健康状况一无所知。我们最近 报道称，产前酒精暴露(PAE)会导致颅脑血流量的长期改变 以及成年后急性缺血性损伤后功能恢复的减慢。这表明PAE是一种 脑血管疾病以及痴呆症和阿尔茨海默病的重要危险因素 (Ad)。年轻的PAE大鼠也表现出认知缺陷，更重要的是，抑郁相关行为增加 这些都是AD的早期预测指标。因此，在这些研究中，我们将利用转基因TgF344-AD大鼠 它在衰老过程中发展AD病理，以验证PAE将加速脑血管的假设 损害、行为功能障碍和AD相关脑部损害的积累，导致早产 衰老。此外，我们还将专门测试雄性和雌性PAE后代在积累方面是否存在差异 与AD相关的解剖学和神经行为病理学。我们将实施一个蒸汽室模型 重复PAE，以实现持续的暴饮式母体暴露发作，跨越胎儿神经源性 句号。PAE和对照后代将从年轻的成年人到15个月大的婴儿通过超声波进行评估 由一组认知功能障碍和行为分析小组进行的颅脑定向血流成像 抑郁症的表型，以及AD病理的一组组织学分析。 研究人员在他们的领域中有合作和应用实验严谨性的历史 在老龄化和PAE模型方面的互补专业知识，这支持拟议研究的可行性。 这些研究具有重要意义，因为它们解决了关于早期生活之间联系的关键知识差距 逆境，即PAE，以及AD的发病。我们预计，如果这些研究确实将PAE与加速AD联系起来 病理学，它们将有助于将FASD重新定义为一种过早衰老的疾病，并加强 研究将PAE与衰老联系起来的机制，以及解除这种联系的干预措施。