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: 10682578
• 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/10682578
• 关键词: AMPA Receptors; Acceleration; Adolescent; Adult; Affect; Age; Alcohol-Related Disorders; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; 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; 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; 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; 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; neuropsychiatric symptom; novel; optogenetics; patch clamp; pharmacologic; 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