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.

在阿尔茨海默氏病（AD）患者的皮质中，降低了突触前胆碱能神经末端的一些标记，例如胆碱乙酰转移酶（CHAT）。同样，在帕金森氏病（PD）中认识到基底神经节中多巴胺能指数的减少。这些神经化学变化与AD认知障碍的严重程度以及PD中的锥体外特征相关。人们普遍认为，这种标记损失反映了基础前脑胆碱能神经元的损失及其在AD和大量NIGRA多巴胺能神经元中的终末项目及其终端的损失。在我们的实验室中获得的结果表明，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，并且不受调节性变化的影响，响应于突触的改变或药物治疗。这些转运蛋白现在可以通过配体结合和免疫组织化学以及具有正电子或单光子发射计算机断层扫描的体内在体外进行测量。我们最近确定，与聊天活动的减少相比，在AD皮层和海马中差异保留的囊泡乙酰胆碱转运蛋白（VACHT）。这与实验动物的结果形成鲜明对比，在实验动物中，隔膜 - 海马轴切开术导致海马形成完全丧失了vacht。这些结果结合在一起，表明AD中的基础前脑胆碱能神经元没有聊天措施所暗示的那么耗尽，并且皮质胆碱能神经支配可能比以前所欣赏的更好。当前建议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后神经化学表型。我们将确定细胞体和神经末端损失在基础前脑对脑皮质胆碱能系统以及中脑至纹状体多巴胺能系统中，采用组织学，配体结合，免疫组织化学和mRNA杂交技术的组合。 我们预计胆碱能和多巴胺能病理的明显，特异性和相关的模式将在AD，Lewy身体痴呆症和PD中找到。这些模式可能会说明AD和相关痴呆症中神经化学病理学的先前报道中的某些明显差异，并且可以为可能的常见和不同的痴呆症病理生理机制提供重要的见解。