VULNERABILITY AND COMPENSATION OF DOPAMINE SYSTEMS IN ALZHEIMER'S AND AGING

阿尔茨海默病和衰老中多巴胺系统的脆弱性和补偿

• 批准号: 6098260
• 负责人: Eric K Richfield
• 金额: --
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098260
• 关键词: 6 hydroxydopamine; Alzheimer's disease; Parkinson's disease; aging; autoradiography; brain mapping; cerebral cortex; cholecystokinin; corpus striatum; dopamine receptor; experimental brain lesion; extrapyramidal disorder; gene expression; high performance liquid chromatography; hippocampus; human tissue; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rat; methylphenyltetrahydropyridine; molecular pathology; neural plasticity; neurotensin; neurotoxins; postmortem; substantia nigra; tegmentum; tyrosine 3 monooxygenase

Abnormalities of the dopamine (DA) neuron system are present in several types of dementia and in normal aging. The two most common degenerative disorders of the elderly, Parkinson's disease (PD) and Alzheimer's disease AD), both have abnormalities of this system, capable of producing clinical symptoms. Dysfunction of the DA system has been implicated in causing a variety of clinical symptoms including the well known motor abnormalities in PD, but also a variety of cognitive, memory, affective, and behavioral symptoms. Neuropathological findings in the substantia nigra suggest that these neurons are differentially lost depending on location, pigmentation, and projection area. Recent studies in rodents and primates demonstrate that the DA system is very widely distributed in the cerebral cortex, as well as in the hippocampus and amygdala, providing a neuroanatomical substrate for influencing diverse cerebral functions. Animal models of DA dysfunction reveal that DA neurons are also differentially vulnerable to neurotoxins and are capable of recovery and compensation under different conditions. The initial objectives of this proposal are to study the differential vulnerability and mechanisms of DA recovery and compensation in two animal models of DA dysfunction. Both the mesostriatal and mesolimbocortical systems will be addressed to determine if these systems are differentially affected and relate these systems to higher cerebral functions relevant to man. Initial mouse studies will be done to determine whether subsets or regions of DA neurons are differentially sensitive to the neurotoxin MPTP. Recovery or compensation of DA indices will be examined over time in this model and in the rat 6-OHDA model to determine possible mechanisms for this compensation. Subsequent studies will address factors that may impede or augment forms of recovery and compensation. Brains from lesioned and control animals will be analyzed using a variety of techniques including in situ hybridization histochemistry for the tyrosine hydroxylase (TH), cholecystokinin (CCK), and neurotensin (NT) genes, and neuron counts in the substantia nigra (SN)/ventral tegmental area (VTA), and DA levels, density of the DA uptake complex, tyrosine hydroxylase activity and protein levels in projection areas of the striatum, hippocampus, and cerebral cortex. Results of these studies will serve to guide future studies in human postmortem brains, and may provide information for the design of interventions in man. Brains from patients with AD will be divided into groups of patients with and without extrapyramidal symptoms, while PD brains will be divided into groups with and without dementia. Other clinical factors to be considered in the analysis will include age, age of onset, duration of disease, and clinical severity. The methods employed in the rodent studies will be used, along with additional techniques of counting neuromelanin positive neurons and the use of multiple probes for the variable human TH message, to examine similar issues of differential DA neuronal vulnerability in these different patient groups. Projection areas will be examined to determined if particular area are deficient in DA markers which might correlate with clinical symptomatology. Results of this aim will provide information about the pathophysiology of these disorders, and might suggest rational interventions.

多巴胺(DA)神经元系统的异常出现在几个 痴呆症的类型和正常衰老。两种最常见的退行性疾病 老年人的疾病、帕金森氏病和阿尔茨海默病 AD)，两者都有这一系统的异常，能够产生临床 症状。DA系统功能障碍被认为是导致 各种临床症状，包括众所周知的运动异常 在帕金森病中，还包括各种认知、记忆、情感和行为 症状。黑质的神经病理结果表明 这些神经元根据位置、色素沉着的不同而不同地丢失， 和投影区。 最近对啮齿动物和灵长类动物的研究表明，DA系统是 非常广泛地分布在大脑皮层以及 海马体和杏仁体，提供了神经解剖学基础 影响不同的大脑功能。多巴胺功能障碍的动物模型 揭示多巴胺神经元对神经毒素的易感性也不同 并且能够在不同条件下进行恢复和补偿。 这项建议的最初目标是研究这种差异 两种动物DA恢复和补偿的脆弱性及其机制 多巴胺功能障碍模型。中纹状体和中脑边缘皮质 将对系统进行寻址，以确定这些系统是否存在差异 这些系统受影响并与更高级的大脑功能相关 天哪。将进行初步的鼠标研究，以确定子集或 DA神经元的不同区域对神经毒素MPTP具有不同的敏感性。 DA指数的恢复或补偿将随着时间的推移在本课程中进行审查 模型和大鼠6-OHDA模型，以确定其可能的作用机制 这笔补偿。后续研究将解决可能导致 妨碍或扩大追回和赔偿的形式。大脑来自 将使用各种不同的方法分析受损动物和对照动物 酪氨酸原位杂交组织化学等技术 羟基酶(TH)、胆囊收缩素(CCK)和神经降压素(NT)基因； 黑质(SN)/腹侧被盖区(VTA)神经元计数， 和DA水平、DA摄取复合体密度、酪氨酸羟基酶 纹状体投射区域的活动和蛋白质水平， 海马体和大脑皮层。这些研究的结果将有助于 指导未来对人类死后大脑的研究，并可能提供 为人类干预措施的设计提供信息。 AD患者的大脑将被分成不同的患者组 并且没有锥体外系症状，而帕金森病患者的大脑将分为 痴呆组和非痴呆组。需要考虑的其他临床因素 分析中将包括年龄、发病年龄、病程和 临床严重度。啮齿动物研究中采用的方法如下 与计算神经黑色素阳性的其他技术一起使用 神经元和对可变的人类TH信息的多个探针的使用， 为了研究不同类型DA神经元的易损性 这些不同的患者群体。将对投影区进行检查以 已确定特定地区是否缺少DA标记，这可能 与临床症状相关联。这一目标的结果将提供 关于这些疾病的病理生理学的信息，以及可能 建议进行合理的干预。