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

摘要 这项新的R 01申请题为“产前酒精暴露是否是一个危险因素的发病和进展， AD/ADRD？”是为了回应RFA-AA-20-006“酒精对糖尿病发作和进展的影响”而提交的。 阿尔茨海默病及其相关痴呆症”。首要目标是检验新的假设， 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。 疾病相关性痴呆（ADRD）。事实上，文献中充满了对酒精的流行病学讨论 在成人中的消费作为AD/ADRD的危险因素。然而，产前检查的生物学基础 酒精暴露与成人饮酒不同。到目前为止，流行病学研究还没有 挖掘了产前酒精暴露可能是AD/ADRD发生的诱发因素的前景。 因此，这项建议的前提是，尽管临床前和临床研究已经将产前 酒精暴露于某些神经发育性大脑疾病，无论是否是一个潜在的危险因素， 发展为晚年、成人发作的认知障碍，特别是AD/ADRD，值得研究。为此我们 提出了三个目标，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、皮质形式和功能的影响的专业知识 和行为测试 目的1：检验3xTg-AD胎儿在妊娠早期的暴饮型产前酒精暴露 破坏原始GABA能中间神经元的皮层切向迁移及其在胚胎中的分布 内侧前额叶皮层（mPFC）和海马。 目的2：检验以下假设，即异常切线迁移与生命后期的早熟有关。 依赖于海马的空间学习/记忆缺陷和依赖于mPFC的 产前暴露于酒精的成年3xTg-AD小鼠的行为灵活性。 目的3：检验空间学习/记忆的早熟缺陷和空间学习/记忆的恶化 在患有PAE的3xTg-AD小鼠中，行为灵活性受损与（1）数量改变和/或 GINs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和海马体。 总的来说，这一提议描绘了一个未经探索和创新的方向， 产前酒精暴露的神经发育后果进入AD/ADRD研究领域。的 这些发现有望为分子、细胞和行为之间的平行关系提供新的前景。 产前酒精暴露与AD/ADRD及其干预和治疗。

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.