Neuropathology of the Aging Sympathetic Nervous System

自主神经功能障碍是老年人日益认识到的一个问题。我们已经证明，人类和啮齿动物交感神经系统的衰老特征是独特的、显着增大的终端轴突和突触的可再生发育，并伴有神经轴突营养不良（NAD）的组织病理学表现。我们最近的一些发现在理解与年龄相关的自主神经功能障碍的发病机制方面取得了重大进展，现在我们提出了对可能是人类疾病基础的突触相关事件的集中分析。我们发现，短期的igf - 1或NT-3治疗可显著降低老年大鼠的交感神经ad。与传统观点相反，与年龄相关的交感神经性痴呆并不是一种简单的NGF缺乏性疾病，令人惊讶的是，外源性NGF实际上可能使NAD恶化。自上次提交以来，我们发现自杀式摄入百草枯（PQ），一种产生超氧化物的除草剂，会导致人类交感神经节的自主神经衰竭和NAD的发展，其结构和免疫特征与衰老中发现的相同。我们发现PQ也在大鼠交感神经元培养中产生营养不良的轴突，这有望为提出的与年龄相关的交感NAD的氧化发病机制提供机制见解。基于我们的研究，我们提出NAD是一种独特的神经病理终点，其形成严重干扰突触传递，是氧化性神经末梢损伤和突触适应缺陷共同作用的结果。在目前的研究计划中，我们拟验证以下假设：1)氧化应激引起神经末梢损伤，是年龄相关性NAD发生的初始刺激；2) NAD反映了突触可塑性、侧枝轴突发芽和/或再生的年龄相关缺陷；3)这种缺陷至少部分是继发于与年龄相关的NGF过量和IGF-1和NT-3减少；4) NAD的形成导致神经元间信号传递缺陷和内器官功能障碍。这些实验的结果不仅提供了对自主神经功能障碍的深入了解，而且还提供了对NAD是重要组成部分的各种病理过程的深入了解。

Autonomic dysfunction is an increasingly recognized problem in aging humans. We have demonstrated that aging in both the human and rodent sympathetic nervous system is characterized by the reproducible development of distinctive, markedly enlarged, terminal axons and synapses with the histopathologic appearance of neuroaxonal dystrophy (NAD). We have made several recent discoveries which represent significant advances in understanding the pathogenesis of age-related autonomic dysfunction and now propose a focused analysis of synapse- associated events that may underlie human disease. We have found that short courses of IGF-I or NT-3 result in significant reduction in established sympathetic NAD in aged rats. Contrary to conventional thinking, age-related sympathetic NAD is not a simple NGF deficiency disease and, surprisingly, exogenously administered NGF may actually worsen NAD. Since our last submission, we have discovered that suicidal ingestion of paraquat (PQ), a superoxide-generating herbicide, results in autonomic failure and the development of NAD in human sympathetic ganglia, identical in structure and immunoprofile to that found in aging. We have found that PQ also produces dystrophic axons in cultures of rat sympathetic neurons, which promises to provide mechanistic insights into the proposed oxidative pathogenesis of age-related sympathetic NAD. Based on our studies, we propose that NAD is a distinctive neuropathological end-point whose formation critically interferes with synaptic transmission and results from a combination of oxidative nerve terminal injury and defective synaptic adaptation. We propose in the current research plan to test the following hypotheses: 1) that oxidative stress causes nerve terminal injury and is the initiating stimulus in the development of age-related NAD; 2) that NAD reflects an age-related defect in synaptic plasticity, collateral axonal sprouting and/or regeneration; 3) that this defect is, at least in part, secondary to an age-related excess of NGF and diminished IGF-1 and NT-3; and, 4) that NAD formation leads to defective interneuronal signal transmission and endorgan dysfunction. The results of these experiments should provide insight not only into autonomic dysfunction, but into a variety of pathologic processes in which NAD is a prominent component.