DEGENERATION OF DOPAMINERGIC PATHWAYS

多巴胺能通路的退化

• 批准号: 6098265
• 负责人: JEFFREY N JOYCE
• 金额: $ 21.7万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098265
• 关键词: Alzheimer's disease; Lewy body; Parkinson's disease; antireceptor antibody; autoradiography; brain disorder diagnosis; brain mapping; cell death; dopamine; dopamine receptor; extrapyramidal disorder; genetically modified animals; histochemistry /cytochemistry; histopathology; human tissue; immunocytochemistry; laboratory mouse; mesencephalon; messenger RNA; molecular pathology; neural degeneration; neurofilament

Midbrain dopamine (DA) neurons are susceptible to premature death in both PD and AD, but different populations of neurons are affected. As these populations of neurons provide input to different territories within the striatum there are different patterns of DA loss in the striatum. It is evident that different processes must be involved as LBs do not typically exist in midbrain neurons of AD cases. A significant proportion of AD cases also develop of extrapyramidal symptoms that closely resemble Parkinsonism in PD cases. It has been assumed that they must represent a combination of the two diseases (AD plus PD). However, it is also evident that AD patients developing extrapyramidal symptoms do not show the typical pathology of PD (i.e., accumulation of LBs and cell loss in the substantia nigra), yet show losses of DA transporter sites (DAT) associated with DA terminals within the striatum. Midbrain DA neurons show a complex organization of subgroups of neurons which can be differentiated into different populations based on morphological criteria, neuromelanin content, tyrosine hydroxylase (TH) content, DAT levels, DAT mRNA levels, TH mRNA levels, co-localized neuropeptides and their innervation by different striatonigral afferents. Finally, these populations of neurons provide input to different territories within the striatum and are affected in normal aging, PD and AD in distinctly different ways. Thus, it is unclear what role LBs play in either the vulnerability of midbrain DA neurons to premature death or in the neuronal disturbances within those neurons (e.g., reduced TH protein and TH mRNA). It has also not been identified how the biochemical heterogeneity of the different populations of midbrain DA neurons are related to these same processes. For these reasons this project is designed to characterize how LBs affect midbrain DA neurons by analysis of PD material with radioligand autoradiography, immunoautoradiography and in situ hybridization histochemistry for a variety of proteins and their mRNAs that are characteristic of midbrain DA neurons. Second characterize the age related biological consequences of the progressive accumulation of NF- rich LB-like lesion in midbrain DA neurons of transgenic mice engineered to express a NFH/LacZ fusion protein that causes aggregation of NF into inclusions in neuronal perkarrya. Third, identify if the biochemical heterogeneity of the different populations of midbrain DA neurons is related to neuronal vulnerability in AD and AD with Parkinsonism, since these diseases differ markedly in their susceptibility to DA neuron loss and pathogenesis to DA terminals. Fourth, determine by receptor autoradiography and in situ hybridization histochemistry if the target receptors (for members of the D2 receptor family) of these different populations of midbrain DA neurons are selectively affected in AD, PD and AD with Parkinsonism.

中脑多巴胺（DA）神经元在两者中都易于过早死亡 PD和AD，但神经元的不同种群受到影响。 这样 神经元的种群向内部的不同地区提供了输入 纹状体中有不同的DA损失模式。 这是 显然，必须涉及不同的过程，因为LB通常不会 存在于AD病例的中脑神经元中。 广告中很大一部分 病例还会发展出非常相似的腹膜外症状 PD案例中的帕金森氏症。 已经假定他们必须代表 两种疾病的组合（AD加PD）。 但是，也是 显然，出现腹膜外症状的AD患者未显示 PD的典型病理（即，LBS的积累和细胞损失 底底），但显示了DA运输站点的损失（DAT） 与纹状体内的DA末端相关。 中脑DA神经元 显示一个复杂的神经元亚组的组织 基于形态学分为不同的人群 标准，神经苯胺含量，酪氨酸羟化酶（Th）含量，DAT 水平，DAT mRNA水平，TH mRNA水平，共定位的神经肽和 它们由不同的纹状体传入。 最后，这些 神经元的种群向内部的不同地区提供了输入 纹状体，在正常衰老，PD和AD中受到影响 不同的方式。 因此，尚不清楚lbs在任何一个中的作用 中脑da神经元的脆弱性过早死亡或 这些神经元内的神经元障碍（例如，TH蛋白质降低和 th mRNA）。 还没有确定生化如何 中脑DA神经元不同种群的异质性是 与这些相同的过程有关。 由于这些原因，该项目旨在表征LB的影响 通过分析具有放射性的PD材料的中脑DA神经元 放射自显影，免疫摄影和原位杂交 各种蛋白质及其mRNA的组织化学 中脑DA神经元的特征。 第二个年龄的特征 NF-进行性积累的相关生物学后果 转基因小鼠的中脑DA神经元中的丰富LB样病变。 表达NFH/LACZ融合蛋白，该蛋白会导致NF聚集到 神经元中的夹杂物。 第三，确定是否生化 中脑DA神经元不同种群的异质性是 与帕金森氏症的AD和广告中的神经元脆弱性有关，因为 这些疾病在对DA神经元丧失的敏感性方面明显不同 DA末端的发病机理。 第四，通过受体确定 放射自显影和原位杂交组织化学 这些不同的受体（对于D2受体家族的成员） 中脑DA神经元的种群在AD，PD和 广告帕金森主义。