Differential Expression of Brainstem Neurotransmitters in Alzheimer's Disease and Alzheimer's Dementia Related Diseases

阿尔茨海默病及阿尔茨海默痴呆相关疾病中脑干神经递质的差异表达

• 批准号: 10017149
• 负责人: Arubala Parlapalle Reddy
• 金额: $ 15.08万
• 依托单位: TEXAS TECH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017149
• 关键词: Affect; Aggressive behavior; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Anxiety; Area; Autopsy; Biological Markers; Brain; Brain Stem; Characteristics; Chronic Disease; Cognition; Data; Dementia; Depressed mood; Development; Disease; Disease Progression; Dopamine; Emotions; Enzyme-Linked Immunosorbent Assay; Female; Frontotemporal Dementia; Functional disorder; Gender; Gene Expression; Genes; Goals; Grant; Homeostasis; Human; Hybrids; Individual; Injury; Link; Memory; Mental Depression; Messenger RNA; Metabolic syndrome; MicroRNAs; Molecular; Molecular Disease; Nerve Degeneration; Neurodegenerative Disorders; Neurohormones; Neuronal Plasticity; Neurons; Neurotransmitters; Norepinephrine; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Physiological; Population; Proteins; Quantitative Reverse Transcriptase PCR; RNA; Regulation; Research; Role; Sampling; Satiation; Serotonin; Serum; Signal Transduction; Sleep Wake Cycle; Stress; Stroke; Substantia nigra structure; Syndrome; Tissues; Traumatic Brain Injury; Ventral Tegmental Area; adult neurogenesis; base; brain tissue; cognitive function; comorbidity; depressed patient; differential expression; dimorphism; executive function; experimental study; feeding; gamma-Aminobutyric Acid; glutamatergic signaling; hindbrain; locus ceruleus structure; mRNA Expression; male; mild cognitive impairment; neurogenesis; neuropsychiatry; non-demented; relating to nervous system; synaptogenesis; tau phosphorylation; treatment strategy

Abstract: The purpose of our study is to investigate the role of neurotransmitters, serotonin (5HT), dopamine (DA) and norepinephrine (NE) in the progression and pathogenesis of Alzheimer's disease (AD) and Alzheimer's Dementia Related Diseases (ADRD). Our study is one of the very few focusing on the brainstem neurotransmitter dysfunction defining neurodegenerative disease pathology as polygenic modulation of 5HT, DA and NE. Brainstem is very important area of the brain to assess neurodegeneration and treatment strategies in AD & ADRD and beyond. We are proposing to establish multidimensional biomarkers defining neurodegenerative diseases (NDDs), brain metabolic syndrome (bMets) and depression (NPS) and dissecting AD & ADRD molecular blue prints. Serotonin is important neurotransmitter to define and reverse neurodegenerative pathology in AD, ADRD and beyond i.e., probable reversal of mild cognitive impairment (MCI), cerebral strokes, and traumatic brain injury (TBI) pathologies. Small populations of neurons in hindbrain area characterized to express 5HT further define important pathological significance in NDDs and NPSs. Molecular links among 5HT, DA and NE in the brainstem are not completely understood and further how mRNA levels and microRNAs altered from non-demented state to MCI state, and MCI state to early AD state are unclear. In addition, we still do not know cellular changes that occur from non-demented healthy state to Lowy-body dementia (LBD), TBI, Fronto-temporal dementia (FTD) and depressed individuals with no dementia Therefore, in the current study, we propose to investigate mRNA levels and microRNAs using brainstem tissues – raphe, locus coeruleus and substantia nigra from all 8 groups of tissues mentioned above. To achieve our objective, we use 2 Specific Aims: In Aim 1, we will investigate three important areas of the brain, including rostral to caudal substantia nigra, raphe and locus coeruleus to investigate neurotransmitters (DA/5HT/NE) mRNA expression in healthy subjects, depressed patients, MCI, TBI, LBD, TBI, AD Braak I/II and AD Braak V/VI. Samples from 3 target areas will be hybridized to Clariom D human pico chip and analyze for multiple pathways altered in different diseases. In Aim 2, we will validate differentially expressed mRNA and microRNA data in 8 groups analyzed in Aim 1. Further, using serum samples from all 8 groups and ELISA, we will assess protein levels of differentially expressed mRNAs and microRNAs from Aim 1. The outcome of our study will provide hypothesis generating gene expression and microRNA data, and this new information can be used for long-term R01 grants.

摘要：本研究旨在探讨神经递质5-羟色胺（5-HT）、多巴胺（DA） (DA)和去甲肾上腺素（NE）在阿尔茨海默病（AD）的进展和发病机制中的作用， 阿尔茨海默氏痴呆症相关疾病（ADRD）。我们的研究是少数几个关注脑干的研究之一 神经递质功能障碍将神经变性疾病病理学定义为5 HT的多基因调节， DA和NE。脑干是评估神经退行性变和治疗的重要脑区 在AD和ADRD及其他领域的战略。我们建议建立多维生物标志物， 神经退行性疾病（NDD）、脑代谢综合征（bMets）和抑郁症（DEAD）以及解剖 AD和ADRD分子蓝图。血清素是定义和逆转的重要神经递质 AD、ADRD及以上的神经退行性病理学，即，轻度认知障碍可能逆转 (MCI)脑中风和创伤性脑损伤（TBI）病理。后脑神经元的小群体 5 HT在NDD和NPS中的表达进一步明确了其重要的病理意义。 脑干中5 HT、DA和NE之间的分子联系尚不完全清楚， 从非痴呆状态到MCI状态，从MCI状态到早期AD状态，mRNA水平和microRNA发生变化 不清楚。此外，我们仍然不知道从非痴呆的健康状态到痴呆的健康状态发生的细胞变化。 低体痴呆（LBD）、TBI、额颞叶痴呆（FTD）和无痴呆的抑郁个体 因此，在目前的研究中，我们建议使用脑干研究mRNA水平和microRNA， 组织-来自上述所有8组组织的中缝、蓝斑和黑质。到 实现我们的目标，我们使用2个具体目标：在目标1，我们将研究大脑的三个重要区域， 包括黑质、中缝和蓝斑的头尾侧，以研究神经递质 (DA/5 HT/NE）健康受试者、抑郁症患者、MCI、TBI、LBD、TBI、AD Braak I/II和 AD Braak V/VI.来自3个目标区域的样本将与Clariom D人类皮科芯片杂交，并分析 不同疾病中的多种途径发生改变。在目标2中，我们将验证差异表达的mRNA， 目标1中分析的8组中的microRNA数据。此外，使用来自所有8组的血清样品和ELISA，我们 将评估来自Aim 1的差异表达的mRNA和microRNA的蛋白质水平。美国大 研究将提供产生基因表达和microRNA数据的假设，这些新信息可以 用于长期R 01赠款。