DEGENERATION OF DOPAMINERGIC PATHWAYS

多巴胺能通路的退化

基本信息

批准号：
6267475
负责人：
JEFFREY N JOYCE
金额：
$ 20.88万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-05-01 至 1999-04-30
项目状态：
已结题

项目摘要

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）神经元在两种情况下都容易过早死亡 PD 和 AD，但不同的神经元群体受到影响。正如这些神经元群向不同区域提供输入纹状体中 DA 损失有不同的模式。这是显然，必须涉及不同的流程，因为 LB 通常不涉及存在于 AD 病例的中脑神经元中。 AD 的很大一部分病例还出现锥体外系症状，与 PD病例中的帕金森症。假设他们必须代表两种疾病的组合（AD 加 PD）。然而，这也是显然，出现锥体外系症状的 AD 患者并未表现出 PD 的典型病理学（即 LB 积累和细胞丢失）黑质），但显示 DA 转运位点 (DAT) 丢失与纹状体内的 DA 终端相关。中脑多巴胺神经元显示神经元亚群的复杂组织，可以根据形态区分为不同的种群标准、神经黑色素含量、酪氨酸羟化酶 (TH) 含量、DAT 水平、DAT mRNA 水平、TH mRNA 水平、共定位神经肽和它们受到不同纹状体黑质传入神经的支配。最后，这些神经元群向不同区域提供输入纹状体并在正常衰老过程中受到影响，PD 和 AD 的影响明显不同的方式。因此，尚不清楚 LB 在这两种情况中扮演什么角色。中脑 DA 神经元容易过早死亡或这些神经元内的神经元紊乱（例如，TH 蛋白减少和 TH mRNA）。目前还不清楚生化作用是如何发生的。不同中脑 DA 神经元群体的异质性与这些相同的过程相关。由于这些原因，该项目旨在描述 LB 如何影响通过使用放射性配体分析 PD 材料来分析中脑 DA 神经元放射自显影、免疫放射自显影和原位杂交多种蛋白质及其 mRNA 的组织化学中脑 DA 神经元的特征。二、年龄特征 NF-逐渐积累的相关生物学后果转基因小鼠中脑 DA 神经元中富含 LB 样病变表达 NFH/LacZ 融合蛋白，导致 NF 聚集成神经元 perkarrya 中的内含物。三、鉴别生化是否不同中脑 DA 神经元群的异质性为与 AD 和 AD 帕金森病的神经元脆弱性有关，因为这些疾病对 DA 神经元丢失的易感性显着不同以及 DA 末端的发病机制。四、由受体决定放射自显影和原位杂交组织化学如果目标这些不同的受体（对于 D2 受体家族的成员）中脑 DA 神经元群体在 AD、PD 和患有帕金森症的AD。