PRESYNAPTIC NEUROCHEMICAL MARKERS

突触前神经化学标志物

• 批准号: 6216978
• 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: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6216978
• 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.

阿尔茨海默病 (AD) 患者皮质中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) 减少。同样，帕金森病 (PD) 中基底神经节多巴胺能指数的降低也被认为是存在的。这些神经化学变化与 AD 认知障碍的严重程度以及 PD 的锥体外系特征相关。这种标记物的丢失被广泛认为反映了 AD 中基底前脑胆碱能神经元及其末端项目的丢失以及 PD 中大量黑质多巴胺能神经元及其纹状体末端的丢失。我们实验室获得的结果表明，一类相对较新的突触标记物，即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，并且不受因突触活动改变或药物治疗而引起的调节变化的影响。现在可以通过配体结合和免疫组织化学在体外测量这些转运蛋白，并通过正电子或单光子发射计算机断层扫描在体内测量这些转运蛋白。我们最近确定，与 ChAT 活性的减少相比，AD 皮层和海马中的囊泡乙酰胆碱转运蛋白 (VAChT) 的保存存在差异。这与实验动物的结果形成鲜明对比，在实验动物中，间隔海马轴突切除术导致海马结构中 VAChT 完全丧失。综合起来，这些结果表明 AD 中的基底前脑胆碱能神经元并不像 ChAT 测量所显示的那样耗尽，并且皮质胆碱能神经支配的结构可能比以前认为的保存得更好。当前提案中的实验将进一步表征神经退行性痴呆症中皮质下胆碱能和多巴胺能投射系统的死后神经化学表型。我们将结合组织学、配体结合、免疫组织化学和 mRNA 杂交技术，确定基底前脑至大脑皮层胆碱能系统和中脑至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，在 AD、路易体痴呆和 PD 中将发现胆碱能和多巴胺能病理的独特、特定和相互关联的模式。这些模式可能解释了先前关于 AD 和相关痴呆症的神经化学病理学报告之间的一些明显差异，并且可能为痴呆疾病可能的常见与不同病理生理机制提供重要见解。