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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

项目概要/摘要阿尔茨海默氏病 (AD) 是导致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）引起的精神残疾或尽管理论上 PAE 引起的精神疾病是可以预防的，但每 1000 名活产婴儿中就有 10 人患有这种疾病。据报道，在广泛的 PAE 和 AD 中，PAE 的患病率高达 10%-16.3%。相关症状、进行性认知障碍已得到专门研究，但有限。通过可用药物缓解这些患者的症状表明缺乏对神经元的了解底物，尤其是 PAE 和/或 AD 相关的神经精神症状 (NPS)，这一点已被广泛接受。冷漠是 PAE 和 AD 中排名最高的 NPS，是通过遗传和环境之间的相互作用而产生的 PAE 被认为是对大脑的环境损害，而 AD 的高危基因则被认为是。被确定为促进 NPS 发生的首要遗传因素，同时预期寿命延长了 8-。美国近50年10年PAE病史与AD高危人群交互作用评估分子、突触、回路和行为水平上的基因是非常紧迫的。伏隔核（NAc）被重新捕获作为介导突触损失和具有 AD 高风险和 PAE 病史的受试者的低动机表型在该提案中，三个具体的。目标旨在首先评估然后修改突触 CP-AMPAR (Aim1) 和兴奋性突触 NAc 中的接触（目标 2），以及 F344 野生型与转基因 AD 大鼠在我们的希望不仅是填补我们理解上的空白。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目标诊所治疗受影响的患者。