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？

基本信息

批准号：
10622587
负责人：
Hermes H Yeh
金额：
$ 41万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
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/10622587
关键词：
3xTg-AD mouse Acute Adult Affect Age Age Months Alcohol consumption Alcohols Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Alzheimer&apos 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 Impaired cognition Impairment Individual Interneurons Intervention Investigation Label Learning Life Light Link Literature Longevity Medial Mediating Memory Molecular Movement Mus Neuroanatomy 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 Synaptic Transmission Testing Video Microscopy adverse outcome autism spectrum disorder 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 timeline

项目摘要

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 申请题为“产前酒精暴露是否是妊娠期酒精中毒发病和进展的危险因素” AD/ADRD？”是为了回应 RFA-AA-20-006“酒精对疾病发生和进展的影响”而提交的。 “阿尔茨海默病及其相关痴呆症”的首要目标是检验以下新假设：产前酒精暴露可能是诱发阿尔茨海默病（AD）和阿尔茨海默病的危险因素事实上，文献中充满了关于酒精的流行病学讨论。然而，成人消费是 AD/ADRD 的危险因素。迄今为止，酒精暴露与成人饮酒不同，尚未有流行病学研究。推测产前酒精暴露可能是 AD/ADRD 的诱发因素。因此，该提议的前提是，虽然临床前和临床研究已将产前酒精暴露会导致某些神经发育性脑部疾病，无论它是否是潜在的危险因素晚年发生的、成人发病的认知障碍，特别是 AD/ADRD，值得研究。提出三个目标，采用年龄匹配的雄性和雌性 3xTg-AD 小鼠，并利用我们的组合研究产前酒精暴露对皮质生成、皮质形态和功能影响的专业知识和行为测试。目标 1：检验 3xTg-AD 胎儿在妊娠早期暴饮型产前酒精暴露的假设破坏原始 GABA 能中间神经元的皮质瓣切向迁移及其在胚胎中的分布内侧前额皮质 (mPFC) 和海马体。目标 2：检验以下假设：异常切向迁移与晚年性早熟有关海马依赖性空间学习/记忆的缺陷和 mPFC 依赖性的损伤加剧产前暴露于酒精的成年 3xTg-AD 小鼠的行为灵活性。目标 3：检验空间学习/记忆早熟缺陷和加剧的假设患有 PAE 的 3xTg-AD 小鼠行为灵活性受损与 (1) 数量改变和/或 GIN 的分布和/或 (2) 异常抑制性 GABA 能和兴奋性谷氨酸能神经传递 mPFC 和海马体。总体而言，该提案描绘了一个未经探索的创新方向，但会带来不利的影响产前酒精暴露对神经发育的影响进入 AD/ADRD 研究领域。研究结果有望为分子、细胞和行为之间的相似性提供新的视角。产前酒精暴露与 AD/ADRD 及其干预和治疗。