Nelson Phillip G
National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, MD 20892, USA.
Curr Alzheimer Res. 2005 Dec;2(5):497-506. doi: 10.2174/156720505774932232.
During normal development of the nervous system, a major reduction occurs in the initially excessive number of neurons and synapses. This "pruning" process is heavily influenced by patterns of electrical activity in the synaptic circuits being pruned. Many of the cell biological and molecular mechanisms involved in this activity-dependent modification of nervous system structure and function have been explicated, and the area is one of intense study. Similarly, an explosive increase has occurred in knowledge about the molecular pathogenesis of Alzheimer disease (AD). There are significant mechanistic commonalities between the normal neurodevelopmental process and development of AD. We hypothesize that abnormalities in neural activity patterns, or in the coupling between neural activity and maintenance of neurons and synaptic circuits, may be a key determinant in the pathogenesis of AD that is late in onset, sporadic in nature, and in which the genes for the presenilins and the beta amyloid precursor protein are normal. Behavioral data suggests that an active, socially engaged life-style may be associated with a reduced risk for AD. If so, mechanisms linking neural activity with synaptic circuit integrity are probably involved and provide a target for ameliorative pharmacological intervention.
在神经系统的正常发育过程中，最初数量过多的神经元和突触会大幅减少。这种“修剪”过程受到正在被修剪的突触回路中电活动模式的严重影响。许多参与这种依赖活动的神经系统结构和功能修饰的细胞生物学和分子机制已被阐明，并且该领域是一个深入研究的领域。同样，关于阿尔茨海默病（AD）分子发病机制的知识也有了爆炸性增长。正常神经发育过程与AD的发展之间存在显著的机制共性。我们假设神经活动模式的异常，或神经活动与神经元及突触回路维持之间的耦合异常，可能是AD发病机制中的一个关键决定因素，AD起病较晚、本质上是散发性的，且早老素和β淀粉样前体蛋白的基因是正常的。行为数据表明，积极参与社交的生活方式可能与降低AD风险有关。如果是这样，将神经活动与突触回路完整性联系起来的机制可能参与其中，并为改善性药物干预提供了一个靶点。
