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: 10461049
• 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/10461049
• 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; Early Onset Alzheimer 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; 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; antagonist; 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.

项目总结/摘要 阿尔茨海默病（AD）是痴呆症的最常见原因，影响3-11%的美国老年人。 另一方面，产前酒精暴露（PAE）引起的精神残疾或 发病率为千分之十。虽然从理论上讲，PAE引起的精神疾病是可以预防的， 据报道，PAE的患病率高达10%-16.3%。在广泛的PAE和AD中， 与症状相关的进行性认知损害已被广泛研究。但受限 这些患者的症状缓解可用的药物表明缺乏对神经元的理解， 在某些情况下，这些症状可能与底物，特别是PAE和/或AD相关的神经精神症状（NPS）有关。人们普遍认为， 冷漠是PAE和AD中排名第一的疾病，它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损害，AD高危基因已被发现。 被认为是促进NPSs发病的主要遗传因素。加上预期寿命增加了8- 过去50年中在美国的10年，PAE病史与AD高风险之间相互作用的评价 在分子、突触、电路和行为水平上研究基因是非常紧迫的。Ca 2+渗透性（CP）-AMPARs， 脑桥核（NAc）被假设为介导突触丢失的潜在底物， 在具有AD高风险和PAE病史的受试者中存在低动机表型。在这份报告中，三个具体 目的是首先评估，然后修改，突触CP-AMPAR（Aim 1）和兴奋性突触 接触（目标2）在NAc，和动机水平（目标3）在F344野生型与转基因AD大鼠在 青少年、早期成人和中年阶段。我们的希望不仅是填补我们理解的差距， 与AD和PAE相关的冷漠的神经机制，而且还发现了新的神经生物学靶点， 治疗受影响的病人。