Neuropathology of the Aging Sympathetic Nervous System

自主神经功能障碍是越来越多人认识到的老龄化问题。我们已经证明，在人类和啮齿动物的交感神经系统中，衰老的特征是具有神经轴索营养不良(NAD)的组织病理学表现的独特的、显著增大的终末轴突和突触的可重复发展。我们最近的几项发现代表了在理解年龄相关自主神经功能障碍的发病机制方面取得的重大进展，现在提出了对可能导致人类疾病的突触相关事件的重点分析。我们发现短疗程的IGF-I或NT-3可显著减少老年大鼠已建立的交感神经NAD。与传统思维相反，与年龄相关的交感性NAD并不是一种简单的NGF缺乏症，令人惊讶的是，外源性使用NGF实际上可能会使NAD恶化。自从我们上一次提交以来，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，导致自主神经衰竭和人类交感神经节NAD的发展，在结构和免疫模式上与衰老中发现的相同。我们发现PQ还在培养的大鼠交感神经元中产生营养不良的轴突，这有望为年龄相关交感神经NAD的氧化发病机制提供机制方面的见解。根据我们的研究，我们认为NAD是一个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。我们在目前的研究计划中提出以下假设：1)氧化应激导致神经末梢损伤，是年龄相关NAD发展的初始刺激；2)NAD反映了与年龄有关的突触可塑性、侧枝轴突萌发和/或再生方面的缺陷；3)这种缺陷至少部分地继发于与年龄相关的NGF过量和IGF-1和NT-3的减少；以及，4)NAD的形成导致神经元间信号传递缺陷和内脏功能障碍。这些实验的结果不仅应该提供对自主神经功能障碍的洞察，而且应该提供对NAD是其中一个重要组成部分的各种病理过程的洞察。

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.