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

摘要 这一新的R01应用程序的标题是：产前酒精暴露是否是糖尿病发生和发展的危险因素 AD/ADRD？“是针对RFA-AA-20-006《酒精对糖尿病的发生和发展的影响》提交的 阿尔茨海默病及其相关痴呆症“。首要目标是测试新的假设，即 产前酒精暴露可能是阿尔茨海默病(AD)和阿尔茨海默氏症的危险因素 疾病相关性痴呆(ADRD)。的确，文献中充斥着关于酒精的流行病学讨论。 成人消费是AD/ADRD的危险因素。然而，产前的生物学基础 酒精接触与成人饮酒是不同的。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的易感因素的前景。 因此，这项建议的前提是，尽管临床前和临床研究已将产前 酒精暴露于某些神经发育性大脑障碍，无论它是否为 发展为老年、成人发病的认知障碍，特别是AD/ADRD，值得研究。为此，我们 提出三个目标，使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门知识 和行为测试。 目的1：检验妊娠早期3xTg-AD胎儿暴饮型产前酒精暴露的假设 干扰原始GABA能中间神经元的皮质顶叶切向迁移及其在胚胎中的分布 内侧前额叶皮质(MPFC)和海马体。 目的2：检验这样一种假设，即异常的切向迁移与晚年的性早熟有关 海马区依赖的空间学习/记忆缺陷和mPFC依赖的加重损害 胎儿期酒精暴露的成年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 患有PAE的3xTg-AD小鼠的行为灵活性受损与(1)数量和/或 GINS和/或(2)异常抑制性GABA能和兴奋性谷氨酸能神经递质在脑内的分布 MPFC和海马体。 总体而言，这项提议描绘了一个未经探索和创新的方向，带来了不利的 将产前酒精暴露的神经发育后果纳入AD/ADRD研究领域。这个 这些发现有望为研究人与人之间的分子、细胞和行为平行提供新的前景 产前酒精暴露与AD/ADRD及其干预治疗

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.