The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: Recent challenges and their implications for novel drug development
The cholinergic hypothesis of age and Alzheimer's disease-related cognitive deficits: Recent challenges and their implications for novel drug development
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DOI：
10.1124/jpet.102.041616
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发表时间：
2003-09-01
影响因子：
3.5
通讯作者：
Buccafusco, JJ
中科院分区：
文献类型：
--
作者：
Terry, AV;Buccafusco, JJ
胆碱能假说最初是在20多年前提出的，它表明大脑中含有乙酰胆碱的神经元功能障碍在很大程度上导致了老年和阿尔茨海默病（AD）患者的认知能力下降。这一前提已成为迄今为止大多数阿尔茨海默病治疗策略和药物开发方法的基础。然而，最近对轻度认知障碍或早期AD患者大脑的研究表明，在这些患者中，胆碱乙酰转移酶和/或乙酰胆碱酯酶活性不受影响（甚至上调），导致一些人质疑这一假设的有效性，以及使用胆碱模拟剂治疗这种疾病的基本原理，特别是在早期阶段。这些挑战主要基于对死后酶活性的分析，应该在已知存在于衰老和AD的广泛胆碱能异常范围内进行正确看待和评估。老年人和阿尔茨海默病患者的死后和死前研究以及动物实验的结果表明，一系列胆碱能异常，包括胆碱转运、乙酰胆碱释放、烟碱和毒蕈碱受体表达、神经营养因子支持以及轴突转运的改变，都可能导致衰老和阿尔茨海默病患者的认知异常。胆碱能异常也可能导致非认知行为异常以及AD中毒性神经斑块的沉积。因此，基于胆碱能的策略可能仍然是有效的一种合理的药物开发方法，用于治疗阿尔茨海默病和其他形式的痴呆。
The cholinergic hypothesis was initially presented over 20 years ago and suggests that a dysfunction of acetylcholine containing neurons in the brain contributes substantially to the cognitive decline observed in those with advanced age and Alzheimer's disease (AD). This premise has since served as the basis for the majority of treatment strategies and drug development approaches for AD to date. Recent studies of the brains of patients who had mild cognitive impairment or early stage AD in which choline acetyltransferase and/or acetylcholinesterase activity was unaffected (or even up-regulated) have, however, led some to challenge the validity of the hypothesis as well as the rationale for using cholinomimetics to treat the disorder, particularly in the earlier stages. These challenges, primarily based on assays of post mortem enzyme activity, should be taken in perspective and evaluated within the wide range of cholinergic abnormalities known to exist in both aging and AD. The results of both post mortem and antemortem studies in aged humans and AD patients, as well as animal experiments suggest that a host of cholinergic abnormalities including alterations in choline transport, acetylcholine release, nicotinic and muscarinic receptor expression, neurotrophin support, and perhaps axonal transport may all contribute to cognitive abnormalities in aging and AD. Cholinergic abnormalities may also contribute to noncognitive behavioral abnormalities as well as the deposition of toxic neuritic plaques in AD. Therefore, cholinergic-based strategies will likely remain valid as one approach to rational drug development for the treatment of AD other forms of dementia.