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.

一些突触前胆碱能神经末梢的标志物，如胆碱乙酰转移酶(ChAT)，在阿尔茨海默病(AD)患者的大脑皮质中降低。同样，在帕金森氏病(PD)中，基底节多巴胺能指数的减少也被认为是存在的。这些神经化学变化与AD患者认知损害的严重程度和PD患者的锥体外系特征有关。这种标志物的丢失被广泛认为反映了AD时基底前脑胆碱能神经元及其终末投射的丢失，以及PD时黑质多巴胺能神经元及其纹状体终末的丢失。我们实验室的研究结果表明，一类相对较新的突触标志物--囊泡性神经递质转运体，是神经病理条件下突触终末丢失的定量标志物，不受突触活性改变或药物治疗反应的调节变化的影响。这些转运蛋白现在可以通过配基结合和免疫组织化学在体外进行测量，也可以通过正电子或单光子发射计算机断层扫描在体内进行测量。我们最近发现，与ChAT活性降低相比，囊泡乙酰胆碱转运体(Vacht)在AD皮质和海马区的差异保存。这与实验动物的结果形成鲜明对比，在实验动物中，隔-海马轴切断术导致海马结构中的Vacht完全丧失。综上所述，这些结果表明，AD患者的基底前脑胆碱能神经元并不像ChAT指标所显示的那样枯竭，皮质胆碱能神经可能比之前所认为的更好地保存了结构。目前提议的实验将进一步表征神经退行性痴呆患者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-大脑皮层胆碱能系统和中脑-纹状体-多巴胺能系统中细胞体和神经末梢丢失之间的关系。我们预计，在AD、路易体痴呆和帕金森病中会发现不同的、特定的和相互关联的胆碱能和多巴胺能病理模式。这些模式可能解释了先前关于AD和相关痴呆的神经化学病理报告中的一些明显差异，并可能为痴呆疾病可能的共同或不同的病理生理机制提供重要的见解。