Targets for Alzheimer's disease research: from basic mechanisms to rational therapies.
Targets for Alzheimer's disease research: from basic mechanisms to rational therapies.
复制标题
阿尔茨海默病研究目标：从基本机制到合理治疗。
DOI：
10.1016/0197-4580(94)90195-3
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发表时间：
1994
影响因子：
4.2
通讯作者：
Gandy,S
中科院分区：
文献类型：
--
作者：
Gandy,S
在过去的二十年里，人们对阿尔茨海默病（AD）的认识取得了非凡的进展。随着中枢胆碱能系统的相对选择性脆弱性的发现，这个时代开始了（9）。通过阐明表征该疾病的结构性神经病理学病变的分子组分，提供了其他线索（1，12，14，19，31，35，44）。在过去的十年中，特别令人兴奋和鼓舞的进展来自一个新领域的发展-AD的分子遗传学。AD与唐氏综合征的关联首次表明可能存在重要的遗传贡献（54），进一步研究继续加强这种关联（3，5，37）;在不到10年的时间里，AD遗传学已经发现了阿尔茨海默病基因（13，22）和分子风险因素（7，8，47）。与大多数活跃的科学研究一样，存在争议，许多问题仍有待解决。此外，由于这项调查的重点是一种导致人类发病和死亡的疾病，因此不断需要进行反思，评估我们自己的努力，并为公众和患者提供准确的信息。这一努力很可能是由寻求合理的（而不是经验性的）治疗干预来推动的，这一概念在科学上是不言而喻的，但事实上，在临床医学实践中并不那么明显。第一个出现在AD管理中的合理治疗是基于纠正中枢胆碱能缺陷的努力（10，50）。胆碱能替代已成为主要的AD药物靶点，至少部分地基于该策略与帕金森病（PD）中成功的多巴胺能替代的潜在相似性。现在人们似乎普遍认为，在许多方面，AD是一种比PD更复杂的疾病，因为AD最终会影响多个大脑区域和许多神经递质系统。然而，在AD早期，胆碱能缺陷的严重程度与其他递质缺陷相比相对过度。因此，在AD的早期阶段可能有一个治疗机会窗口，在此期间胆碱能替代品确实有益（18）。人们还必须认识到，即使在最好的情况下，基于胆碱能的AD症状缓解可能非常有限（即，持续几个月的益处）。没有直接的证据表明胆碱能治疗攻击的根本原因或改变疾病的进展，虽然需要额外的基础工作之前，可以确定。
THE PAST two decades have brought extraordinary progress in the understanding of Alzheimer disease (AD). The era was ushered in by the discovery of the relatively selective vulnerability of the central cholinergic system (9). Additional leads were provided by the elucidation of the molecular components of the structural neuropathological lesions that characterize the disease (1, 12, 14, 19, 31, 35, 44). In the last decade, particularly exciting and encouraging advances arose from the development of a new field--the molecular genetics of AD. The possible existence of important genetic contributions to AD was first suggested by the association of AD with Down syndrome (54), an association that continues to be strengthened by further study (3, 5, 37); in less than 10 years, AD genetics has yielded discoveries of Alzheimer disease genes (13, 22) and molecular risk factors (7, 8, 47). As with most active scientific inquiry, controversies exist and many issues remain to be resolved. Furthermore, because the focus of this investigation is a disease that is a leading cause of human morbidity and mortality, there is a constant need and demand for reflection, to assess our own efforts as well as to provide the public and our patients with accurate information. This effort is likely to be best driven by a quest for rational (rather than empirical) therapeutic interventions, a concept that is self-evident to many in science but is, in fact, less widely apparent in the practice of clinical medicine.The first rational therapy to emerge in the management of AD was based on an effort to correct the central cholinergic deficit (10, 50). Cholinergic replacement has been a major AD drug target, based, at least in part, on the potential analogy of the strategy with the dopaminergic replacement which had succeeded in Parkinson disease (PD). It seems now widely agreed that AD is, in many ways, a more complex disorder than PD, because AD eventually affects multiple brain regions and many neurotransmitter systems. However, early in AD, the severity of the cholinergic deficit is relatively excessive as compared with other transmitter deficits. Thus, there may well be a window of therapeutic opportunity in the early stages of AD during which time cholinergic replacement is truly beneficial (18). One must also recognize the widely held impression that even under the best circumstances cholinergic-based relief of AD symptoms might be quite limited (ie, benefit persisting for a matter of a few months). There is no direct evidence that cholinergic treatment attacks the fundamental cause or alters the progression of the disease, although additional basic work is required before this can be determined with certainty.