Neuropathology of the Aging Sympathetic Nervous System

自主神经功能障碍是日益认识到的老年人的问题。 我们已经证明，在人类和啮齿类动物的交感神经系统的老化的特点是独特的，显着扩大，终端轴突和突触的组织病理学表现的神经轴索营养不良（NAD）的可再生发展。 我们最近的几项发现代表了对年龄相关性自主神经功能障碍发病机制的理解的重大进展，现在提出了对可能导致人类疾病的突触相关事件的集中分析。 我们已经发现，IGF-I或NT-3的短期疗程导致老年大鼠中已建立的交感神经NAD显著减少。 与传统思维相反，与年龄相关的交感神经NAD不是一种简单的NGF缺乏症，令人惊讶的是，外源性给予NGF实际上可能会恶化NAD。 自我们上次提交以来，我们发现自杀性摄入百草枯（PQ），一种产生超氧化物的除草剂，导致自主神经功能衰竭和人类交感神经节中NAD的发展，与衰老中发现的结构和免疫特征相同。 我们已经发现，PQ也产生营养不良的轴突在大鼠交感神经元的文化，这有望提供机制的见解，提出了与年龄相关的交感神经NAD的氧化发病机制。基于我们的研究，我们提出，NAD是一个独特的神经病理学终点，其形成严重干扰突触传递和氧化神经末梢损伤和有缺陷的突触适应的组合的结果。 本研究拟验证以下假说：1）氧化应激导致神经末梢损伤，是年龄相关性NAD发生的起始刺激; 2）NAD反映了突触可塑性、侧支轴突发芽和/或再生的年龄相关性缺陷; 3）该缺陷至少部分地继发于与年龄相关的过量的NGF和减少的IGF-1和NT-3;以及4）NAD形成导致有缺陷的神经元间信号传递和内器官功能障碍。 这些实验的结果应该提供洞察不仅自主神经功能障碍，但到各种病理过程中，NAD是一个突出的组成部分。

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.