Effects of Prenatal Alcohol Exposure on Alzheimer's Disease-associated Neuropsychiatric Symptoms

项目摘要/摘要 阿尔茨海默病(AD)是导致痴呆症的最常见原因，美国3%-11%的老年人受到影响。 另一方面，估计产前酒精暴露(PAE)导致的精神残疾或 发病率为每1000名活产儿中有10名。尽管理论上PAE引起的精神疾病是可以预防的，但 据报道，PAE的患病率高达10%-16.3%。在广泛的PAE和AD中- 伴随的症状，进行性认知障碍已被广泛研究。然而，有限的 这些患者通过可用药物缓解症状表明缺乏对神经元的了解。 底物，特别是PAE和/或AD相关的神经精神症状(NPSS)。人们普遍认为 冷漠是PAE和AD中排名最高的NPS，它是由遗传和环境之间的相互作用引起的 各种因素。PAE被认为是对大脑的一种环境侮辱，AD高危基因一直被认为是 被认为是促进NPSS发病的首要遗传因素。加上预期寿命增加了8- 美国近50年来PAE病史与AD高危人群相互作用的评价 在分子、突触、回路和行为水平上的基因是非常紧迫的。钙离子通透性(CP)-AMPAR 伏隔核(NAC)被认为是介导突触丢失的潜在底物。 有AD高危和PAE病史的受试者的低动机表型。在这份提案中，有三个具体的 AIMS旨在首先评估并修改突触CP-AMPAR(Aim1)和兴奋性突触 NAC中的接触者(目标2)，以及F344野生型和转基因AD大鼠的动机水平(目标3) 青春期、成年期早期和中年阶段。我们的希望不仅是为了填补我们对 AD和PAE相关冷漠的神经机制，但也发现了新的神经生物学靶点 治疗受影响的病人的诊所。

PROJECT SUMMARY / ABSTRACT Alzheimer’s disease (AD) is the most common cause of dementia, affecting 3–11% of the United States elderly. On the other hand, the estimated incidence of prenatal alcohol exposure (PAE)-induced mental disability or disease is 10 per 1000 live births. Although theoretically PAE-induced mental diseases are preventable, the prevalence of PAE has been reported to be as high as 10%-16.3%. Among a broad spectrum of PAE and AD- associated symptoms, progressive impairment of cognition has been extensively investigated. However, limited symptomatic relief in these patients by available medications demonstrates lack of understanding of the neuronal substrates, especially the PAE and/or AD-associated neuropsychiatric symptoms (NPSs). It is well accepted that apathy, the top ranked NPS in both PAE and AD, arises through interactions between genetic and environmental factors. PAE has been considered an environmental insult to the brain and AD high risk genes have been identified as top genetic factors facilitating the onset of NPSs. Together with the increased life expectancy by 8- 10 years in the USA in the last 50 years, the evaluation of interactions between PAE history and AD high-risk genes at the molecular, synaptic, circuit, and behavioral levels is highly urgent. Ca2+permeable(CP)-AMPARs in the nucleus accumbens (NAc) are hypothesized as the potential substrate in mediating the synaptic loss and the low motivation phenotype in subjects with high risk of AD and a history of PAE. In this proposal, three Specific Aims are designed to first evaluate, and then modify, synaptic CP-AMPARs (Aim1) and excitatory synaptic contacts (Aim 2) in the NAc, and motivation levels (Aim 3) in F344 wild type vs. transgenic AD rats at the adolescent, early adult and middle-aged stages. Our hope is to not only fill the gap in our understanding of neuronal mechanisms of apathy associated with AD and PAE, but also uncover novel neurobiological targets in the clinic to treat affected patients.