Ferreyra-Moyano H, Barragan E
Instituto de Investigacion Medica M. y M. Ferreyra, Cordoba, Argentina.
Int J Neurosci. 1989 Dec;49(3-4):157-97. doi: 10.3109/00207458909084824.
Alzheimer's disease (AD) is considered to be the number one health problem and seems to be reaching epidemic proportion in the USA. The cause of AD is not known, a reliable animal model of the disease has not been found and appropriate treatment of this dementia is wanting. The present review focuses on the possibility that a virus or exogenous toxic materials may gain access to the CNS using the olfactory mucosa as a portal of entry. Anterograde and retrograde transport of the virus/zeolites to olfactory forebrain regions, which receive primary and secondary projections from the main olfactory bulb (MOB) and which, in turn, project centrifugal axons to the MOB, may initiate cell degeneration at such loci. Pathological changes may, thus, be initially confined to projecting and intrinsic neurons localized in cortical and subcortical olfactory structures; arguments are advanced which favor the view that excitotoxic phenomena could be mainly responsible for the overall degenerative picture. Neurotoxic activity may follow infection by the virus itself, be facilitated by loss of GABAergic terminals in olfactory cortex, develop following repeated episodes of physiological long term potentiation (which unmasks NMDA receptors) or be due to excessive release, faculty re-uptake or altered glutamate receptor sensitivity. Furthermore, a reduction in central inhibitory inputs to the MOB might then result in disinhibition of mitral/tufted neurons and enhance the excitotoxic phenomena in the MOB projecting field. Within this context, and in line with recent studies, it is believed that pathology begins at cortical (mainly olfactory) regions, basal forebrain neurons being secondarily affected due to retrograde degeneration. In addition, failure to produce a critical level of neurotrophic factors by a damaged MOB and olfactory cortex, could adversely affect survival of basal cholinergic neurons which innervate both regions. Support for these hypothesis is provided, first, by recent reports on pathological findings in AD brains which seem to involve preferentially the olfactory and entorhinal cortices, the olfactory amygdala and the hippocampus, all of which receive primary or secondary projections from the MOB; secondly, by the presence of severe olfactory deficits in the early stages of the disease, mainly of a discriminatory nature, which points to a malfunction of central olfactory structures.
阿尔茨海默病（AD）被认为是头号健康问题，在美国似乎正呈流行态势。AD的病因不明，尚未找到可靠的该疾病动物模型，且针对这种痴呆症的恰当治疗方法也尚缺。本综述聚焦于病毒或外源性有毒物质可能通过嗅觉黏膜作为进入门户进入中枢神经系统的可能性。病毒/沸石向嗅觉前脑区域的顺行和逆行运输，这些区域接收来自主嗅球（MOB）的一级和二级投射，并且反过来向MOB投射离心轴突，可能在此类位点引发细胞变性。因此，病理变化最初可能局限于位于皮质和皮质下嗅觉结构中的投射神经元和固有神经元；文中提出了一些观点，支持兴奋性毒性现象可能是整体退行性病变主要原因的观点。神经毒性活动可能继发于病毒本身感染，因嗅觉皮质中GABA能终末的丧失而加剧，在反复发生生理性长时程增强（使NMDA受体暴露）后出现，或者是由于谷氨酸过度释放、再摄取功能障碍或谷氨酸受体敏感性改变。此外，对MOB的中枢抑制性输入减少可能随后导致二尖瓣/簇状神经元去抑制，并增强MOB投射区域的兴奋性毒性现象。在此背景下，与近期研究一致，人们认为病理始于皮质（主要是嗅觉）区域，基底前脑神经元因逆行变性而继发受累。此外，受损的MOB和嗅觉皮质未能产生临界水平的神经营养因子，可能对支配这两个区域的基底胆碱能神经元的存活产生不利影响。首先，近期关于AD大脑病理发现的报告为这些假说提供了支持，这些发现似乎优先涉及嗅觉和内嗅皮质、嗅觉杏仁核和海马体，所有这些区域都接收来自MOB的一级或二级投射；其次，疾病早期存在严重的嗅觉缺陷，主要是辨别性的，这表明中枢嗅觉结构功能异常。
