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

产前酒精暴露对阿尔茨海默病相关神经精神症状的影响

• 批准号: 10265600
• 负责人: Yao-Ying Ma
• 金额: $ 39.63万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10265600
• 关键词: AMPA Receptors; Adolescent; Adult; Affect; Age; Alcohol-Related Disorders; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Atrophic; Attention; Behavioral; Biochemical; Brain; Brain region; Caregiver Burden; Caregivers; Cells; Clinic; Cocaine; Data; Dementia; Disabled Persons; Disease; Elderly; Environmental Risk Factor; Evaluation; Excitatory Synapse; Fetal Alcohol Exposure; Fetal alcohol effects; Genetic; Glutamates; Goals; Hippocampus (Brain); Housing; Human; Impaired cognition; Incidence; Institutionalization; Investigation; Laboratory Animals; Learning; Life; Life Expectancy; Light; Live Birth; Locomotion; Measures; Medial; Mediating; Membrane Proteins; Memory; Molecular; Motivation; Neurobiology; Neurons; Nucleus Accumbens; Optics; Output; Pathologic; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Prefrontal Cortex; Presenile Alzheimer Dementia; Prevalence; Psyche structure; Psychological reinforcement; Quality of life; Rattus; Recording of previous events; Reporting; Role; Shock; Slice; Stains; Sucrose; Symptoms; Synapses; Synaptic Transmission; Testing; Transgenic Organisms; United States; Vertebral column; Western Blotting; alcohol exposure; associated symptom; base; behavior test; behavioral phenotyping; care costs; design; disability; early onset; excitotoxicity; exposed human population; foot; high risk; improved; in vivo; indexing; maternal alcohol use; middle age; neural circuit; neuropsychiatric symptom; novel; optogenetics; patch clamp; postsynaptic; premature; presynaptic; presynaptic density protein 95; prevent; protective factors; receptor; recruit; risk variant; success; vesicular glutamate transporter 1

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.

项目摘要 /摘要 阿尔茨海默氏病（AD）是痴呆症的最常见原因，较早影响美国的3-11％。 另一方面，估计的产前酒精暴露事件（PAE）引起的精神障碍或 疾病是每1000个活生生的10个。尽管理论上可以预防PAE引起的精神疾病，但 据报道，PAE的患病率高达10％-16.3％。在广泛的PAE和AD-中 相关符号，认知的进行性损害已得到广泛研究。但是，有限 这些患者通过可用药物的症状缓解表明对神经元缺乏了解 底物，尤其是PAE和/或与AD相关的神经精神症状（NPSS）。很公认 冷漠是PAE和AD中排名最高的NP，是通过遗传和环境之间的相互作用而产生的 因素。 PAE被认为是对大脑的环境侮辱，广告高风险基因已被认为是 被确定为促进NPS发作的主要遗传因素。以及8-的预期寿命增加 在过去的50年中，美国在美国的10年，评估PAE历史与广告高风险之间的相互作用 分子，突触，电路和行为水平的基因非常紧急。 Ca2+渗透性（CP） - ampars in 假设伏隔核（NAC）是介导突触损失和 在AD高风险和PAE病史的受试者中，动机表型低。在此提案中，三个具体 目的旨在首先评估，然后修改突触CP-Ampar（AIM1）和兴奋性突触 NAC中的联系人（AIM 2）以及F344野生型与转基因广告大鼠的动机水平（目标3） 青少年，早期和中年阶段。我们的希望不仅要填补我们对 与AD和PAE相关的冷漠的神经元机制，但也发现了新颖的神经生物学靶标 治疗患者的诊所。