Is prenatal alcohol exposure a risk factor for the onset and progression of AD/ADRD?

产前酒精暴露是 AD/ADRD 发病和进展的危险因素吗？

• 批准号: 10418793
• 负责人: Hermes H Yeh
• 金额: $ 41万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10418793
• 关键词: 3xTg-AD mouse; Acute; Adult; Affect; Age; Age-Months; Alcohol consumption; Alcohols; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Attention; Attention deficit hyperactivity disorder; Behavioral; Biological; Brain; Brain Diseases; Cells; Clinical; Clinical Research; Cognition Disorders; Complex; Data; Dementia; Dependence; Development; Early Diagnosis; Elderly; Electrophysiology (science); Embryo; Epidemiology; Equilibrium; Etiology; Female; Fetal Alcohol Exposure; Fetal Alcohol Spectrum Disorder; Fetal alcohol effects; Fetus; Glutamates; Goals; Hippocampus (Brain); Impaired cognition; Impairment; Individual; Interneurons; Intervention; Investigation; Label; Lead; Learning; Life; Light; Link; Literature; Longevity; Medial; Mediating; Memory; Molecular; Movement; Mus; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Outcome; Parvalbumins; Pilot Projects; Positioning Attribute; Predisposing Factor; Prefrontal Cortex; Pregnancy; Regimen; Reporting; Research; Retrieval; Reversal Learning; Risk Factors; Slice; Somatostatin; Synapses; Testing; Time; TimeLine; Video Microscopy; adverse outcome; autism spectrum disorder; base; behavior test; behavioral impairment; cohort; epidemiology study; experience; experimental study; fetal; flexibility; gamma-Aminobutyric Acid; high risk; innovation; male; maternal alcohol use; migration; mouse model; neurodevelopment; neurotransmission; novel; postnatal; preclinical study; pregnant; prenatal; prospective; response; sex; transmission process

ABSTRACT This new R01 application entitled “Is prenatal alcohol exposure a risk factor for the onset and progression of AD/ADRD?” is submitted in response to RFA-AA-20-006 “Impact of Alcohol on the Onset and Progression of Alzheimer's Disease and Its Related Dementias”. The overarching goal is to test the novel hypothesis that prenatal alcohol exposure may be a risk factor for predisposing Alzheimer's disease (AD) and Alzheimer's Disease-Related Dementia (ADRD). Indeed, the literature is replete with epidemiologic discussions of alcohol consumption in the adult as a risk factor for AD/ADRD. However, the biological underpinnings of prenatal alcohol exposure are distinct from those of adult alcohol consumption. To date, epidemiologic studies have not mined the prospect that prenatal alcohol exposure may be a predisposing factor for developing AD/ADRD. Thus, this proposal rides on the premise that, whereas preclinical and clinical studies have linked prenatal alcohol exposure to certain neurodevelopmental brain disorders, whether or not it is a potential risk factor for developing later-life, adult-onset cognitive disorders, notably AD/ADRD, warrants investigation. To this end, we propose three aims, employing age-matched male and female 3xTg-AD mice and leveraging our combined expertise in investigating the effects of prenatal alcohol exposure on corticogenesis, cortical form and function and behavioral testing. Aim 1: Test the hypothesis that a binge-type prenatal alcohol exposure of 3xTg-AD fetuses early in gestation disrupts corticopetal tangential migration of primordial GABAergic interneurons and their distribution in the embryonic medial prefrontal cortex (mPFC) and hippocampus. Aim 2: Test the hypothesis that the aberrant tangential migration is associated later in life with a precocious deficit in hippocampal-dependent spatial learning/memory and an exacerbated impairment in mPFC-dependent behavioral flexibility in adult 3xTg-AD mice exposed prenatally to alcohol. Aim 3: Test the hypothesis that the precocious deficit in spatial learning/memory and the exacerbated impairment in behavioral flexibility in the 3xTg-AD mice with PAE are associated with (1) altered number and/or distribution of GINs and/or (2) abnormal inhibitory GABAergic and excitatory glutamatergic neurotransmission in the mPFC and hippocampus. Overall, this proposal charts an unexplored and innovative direction that carries the adverse neurodevelopment consequences of prenatal alcohol exposure into the realm of AD/ADRD research. The findings promise to contribute new vistas into the molecular, cellular and behavioral parallelisms between prenatal alcohol exposure and AD/ADRD as well as their intervention and treatment.

抽象的 这个新的R01应用程序名为“是产前酒精暴露的一个危险因素 AD/ADRD？ 阿尔茨海默氏病及其相关痴呆症”。总体目标是检验新的假设 产前酒精暴露可能是易感阿尔茨海默氏病（AD）和阿尔茨海默氏症的危险因素 疾病相关痴呆（ADRD）。确实，文献被酒精的流行病学讨论所取代 成年人的消费是广告/ADRD的危险因素。但是，产前的生物基础 酒精暴露与成人饮酒不同。迄今为止，流行病学研究还没有 开采的前景是，产前酒精暴露可能是发展AD/ADRD的诱人因素。 这是在以下前提下的，尽管临床前和临床研究已将产前联系起来 酒精暴露于某些神经发育脑部疾病，无论它是否是潜在的危险因素 发展后来的成人认知障碍，尤其是AD/ADRD，需要调查。为此，我们 提案三个目标，采用年龄匹配的男性和女性3XTG-AD小鼠并利用我们的总和 研究产前酒精暴露对皮质生成，皮质形式和功能的影响的专业知识 和行为测试。 目标1：检验以下假设：妊娠早期3XTG-AD胎儿暴露产前酒精暴露 原始gabaergic中间神经元的皮质皮层切向迁移及其在胚胎中的分布 培养基前额叶皮层（MPFC）和海马。 目标2：检验以下假设，即异常切向迁移在以后的生活中与早熟相关 海马依赖性空间学习/记忆和MPFC依赖性障碍的赤字 成人3XTG-AD小鼠的行为柔韧性在产前暴露于酒精。 目标3：检验以下假设：空间学习/记忆和恶化的早熟赤字 带有PAE的3XTG-AD小鼠行为灵活性的损害与（1）变化数量和/或 杜松子酒的分布和/或（2）异常的抑制性GABA能和兴奋性谷氨酸能神经传递 MPFC和海马。 总体而言，该提案图表了一个意外而创新的方向，载有对手 产前酒精暴露于AD/ADRD研究领域的神经发育后果。这 调查结果有望在分子，细胞和行为并行之间贡献新的远景 产前酒精暴露和AD/ADRD及其干预和治疗。