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: 10286284
• 负责人: Arubala Parlapalle Reddy
• 金额: $ 15.3万
• 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/10286284
• 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：我们研究的目的是探讨神经递质、血清素（5HT）、多巴胺的作用。 (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 阿尔茨海默氏痴呆相关疾病 (ADRD)。我们的研究是极少数关注脑干的研究之一 神经递质功能障碍将神经退行性疾病病理学定义为 5HT 的多基因调节， DA 和 NE。脑干是评估神经退行性变和治疗的非常重要的大脑区域 AD 和 ADRD 及其他领域的策略。我们建议建立多维生物标志物来定义 神经退行性疾病 (NDD)、脑代谢综合征 (bMet) 和抑郁症 (NPS) 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 及其他疾病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。后脑中的少量神经元 以表达 5HT 为特征的区域进一步明确了 NDD 和 NPS 中的重要病理意义。 脑干中 5HT、DA 和 NE 之间的分子联系尚未完全了解，进一步了解如何 mRNA水平和microRNA从非痴呆状态改变为MCI状态，MCI状态改变为早期AD状态 不清楚。此外，我们仍然不知道从非痴呆健康状态到正常状态之间发生的细胞变化。 低体痴呆 (LBD)、TBI、额颞叶痴呆 (FTD) 和无痴呆的抑郁个体 因此，在当前的研究中，我们建议利用脑干研究 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 为了实现我们的目标，我们使用 2 个具体目标：在目标 1 中，我们将研究大脑的三个重要区域， 包括从头到尾的黑质、中缝和蓝斑以研究神经递质 (DA/5HT/NE) 健康受试者、抑郁症患者、MCI、TBI、LBD、TBI、AD Braak I/II 和 AD 布拉克 V/VI。来自 3 个目标区域的样本将与 Clariom D 人类 pico 芯片杂交并进行分析 不同疾病中多种途径发生改变。在目标 2 中，我们将验证差异表达的 mRNA 和 目标 1 中分析了 8 组的 microRNA 数据。此外，使用所有 8 组的血清样本和 ELISA，我们 将评估目标 1 中差异表达 mRNA 和 microRNA 的蛋白质水平。我们的结果 研究将提供生成基因表达和 microRNA 数据的假设，并且这些新信息可以 用于长期 R01 补助金。

项目成果

Protective effects of a small molecule inhibitor ligand against hyperphosphorylated tau-induced mitochondrial and synaptic toxicities in Alzheimer disease.

小分子抑制剂配体对阿尔茨海默病中过度磷酸化 tau 诱导的线粒体和突触毒性的保护作用。

• DOI: 10.1093/hmg/ddab244
• 发表时间: 2021
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Pradeepkiran,JangampalliAdi;Munikumar,Manne;Reddy,ArubalaP;Reddy,PHemachandra
• 通讯作者: Reddy,PHemachandra