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

摘要：本研究的目的是探讨神经递质、5-羟色胺、多巴胺的作用。 (DA)和去甲肾上腺素(NE)在阿尔茨海默病(AD)进展和发病机制中的作用 阿尔茨海默氏症痴呆相关疾病(ADRD)。我们的研究是为数不多的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的病理定义为5-羟色胺的多基因调节， 达美和内华达州。脑干是评估神经变性和治疗的非常重要的脑区 AD和ADRD及以后的战略。我们建议建立多维生物标记物来定义 神经退行性疾病(NDDS)、脑代谢综合征(BMets)和抑郁症(NPS)与解剖 AD&ADRD分子蓝图。5-羟色胺是定义和逆转的重要神经递质 AD、ADRD及以后的神经退行性病变，即轻度认知功能障碍可能逆转 (MCI)、脑中风和创伤性脑损伤(TBI)病理学。后脑中的少量神经元 以5-羟色胺为特征的区域进一步明确了NDDS和NPSS的重要病理意义。 脑干中5-羟色胺、多巴胺和去甲肾上腺素之间的分子联系尚不完全清楚，以及进一步了解 从非痴呆状态到MCI状态，再从MCI状态到AD早期状态，mRNAs和microRNAs水平发生变化 都不清楚。此外，我们仍然不知道细胞从非痴呆的健康状态到 低体痴呆(LBD)、脑外伤、额-颞叶痴呆(FTD)和无痴呆的抑郁个体 因此，在目前的研究中，我们建议使用脑干来研究mrna水平和microrna。 上述8组组织中的中缝、蓝斑和黑质。至 为了实现我们的目标，我们使用两个具体的目标：在目标1中，我们将研究大脑的三个重要区域， 包括吻侧至黑质尾侧、中缝和蓝斑，以研究神经递质 (DA/5HT/NE)mRNA在正常人、抑郁症患者、MCI、脑外伤、腰背痛、脑外伤、AD Braak I/II和 来自3个靶区的样本将与Clariom D人类微微芯片杂交，并分析 多种途径在不同的疾病中发生改变。在目标2中，我们将验证差异表达的mRNA和 分析了目标1中8个组的microRNA数据。此外，使用所有8个组的血清样本和ELISA，我们 将评估来自Aim 1的差异表达的mRNAs和microRNAs的蛋白质水平。我们的结果 研究将提供假说生成基因表达和microRNA数据，而这些新信息可以 用于长期R01拨款。

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.