PRESYNAPTIC NEUROCHEMICAL MARKERS

突触前神经化学标志物

• 批准号: 6315625
• 负责人: KIRK A. FREY
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6315625
• 关键词: Alzheimer's disease; Lewy body; Parkinson's disease; aging; amyotrophic lateral sclerosis; basal ganglia; biomarker; choline acetyltransferase; corpus striatum; dementia; dopamine; human tissue; immunochemistry; in situ hybridization; laboratory rat; neurochemistry; neuropathology; neuropharmacology; neurotransmitter transport; neurotrophic factors; phenotype; postmortem; substantia nigra; synaptic vesicles

Some markers of presynaptic cholinergic nerve terminals such as the enzyme choline acetyltransferase (ChAT) are reduced in the cortex of Alzheimer's disease (AD) patients. Similarly, reductions in dopaminergic indices in the basal ganglia are recognized in Parkinson's disease (PD). These neurochemical changes correlate with the severity of cognitive impairment in AD and with extrapyramidal features in PD. Such marker losses are widely assumed to reflect losses of basal forebrain cholinergic neurons and their terminal projects in AD and of substantial nigra dopaminergic neurons and their striatal terminals in PD. Results obtained in our laboratories indicate that a relatively new class of synaptic markers, vesicular neurotransmitter transporters, are quantitative markers of synaptic terminal losses in neuropathological conditions and are not affected by regulatory changes in response to altered synaptic activity or drug treatments. These transporters can now be measured in vitro with ligand binding and immunohistochemistry and in vivo with positron- or single photon emission computer tomography. We recently determined that the vesicular acetylcholine transporter (VAChT) in differentially preserved in AD cortex and hippocampus in comparison to reductions in ChAT activity. This contrasts with results in experimental animals where septo-hippocampal axotomy results in a complete loss of VAChT from the hippocampal formation. Combined, these results suggest that basal forebrain cholinergic neurons in AD are not as depleted as ChAT measures suggest, and that cortical cholinergic innervation may be better structural preserved than previously appreciated. Experiments in the current proposal will characterize further the postmortem neurochemical phenotypes of subcortical cholinergic and dopaminergic projection system in neurodegenerative dementing disorders. We will determine the relationships between cell body and nerve terminal losses in the basal forebrain-to-cerebral cortex cholinergic system and in the midbrain-to-striatum dopaminergic system, employing a combination of histological, ligand binding, immunohistochemical, and mRNA hybridization techniques. We anticipate that distinct, specific and inter-related patterns of cholinergic and dopaminergic pathologies will be found in AD, Lewy body dementias, and PD. These patterns may account for some apparent discrepancies among prior reports of neurochemical pathology in AD and related dementias, and may provide important insights into possible common versus differing pathophysiological mechanisms of dementing diseases.

突触前胆碱能神经末梢的一些标志物，如胆碱乙酰转移酶（ChAT）在阿尔茨海默病（AD）患者的皮质中减少。类似地，在帕金森病（PD）中认识到基底神经节中多巴胺能指数的降低。这些神经化学变化与AD的认知功能障碍的严重程度和PD的锥体外系特征相关。这种标志物的损失被广泛认为反映了基础前脑胆碱能神经元和他们的终端项目在AD和大量的黑质多巴胺能神经元和他们的纹状体终端在PD的损失。在我们的实验室中获得的结果表明，一类相对较新的突触标记物，囊泡神经递质转运蛋白，是神经病理条件下突触末端损失的定量标记物，并且不受突触活性改变或药物治疗引起的调节变化的影响。这些转运蛋白现在可以在体外测定配体结合和免疫组织化学和体内正电子或单光子发射计算机断层扫描。我们最近确定，囊泡乙酰胆碱转运蛋白（VAChT）的差异保存在AD皮质和海马相比，减少ChAT活性。这与实验动物的结果形成对比，其中隔-海马轴突切断导致海马结构的VAChT完全丧失。结合起来，这些结果表明，基底前脑胆碱能神经元在AD并不耗尽的ChAT措施建议，皮质胆碱能神经支配可能是更好的结构保存比以前赞赏。本实验将进一步研究神经退行性痴呆患者死后皮质下胆碱能和多巴胺能投射系统的神经化学表型。我们将采用组织学、配体结合、免疫组织化学和mRNA杂交技术相结合的方法，确定基底前脑-大脑皮质胆碱能系统和中脑-纹状体多巴胺能系统中细胞体和神经末梢损失之间的关系。 我们预计，不同的，具体的和相互关联的模式，胆碱能和多巴胺能的病理将被发现在AD，路易体痴呆，PD。这些模式可以解释AD和相关痴呆的神经化学病理学先前报告之间的一些明显差异，并可能提供重要的见解痴呆疾病的可能共同与不同的病理生理机制。