Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.
Nat Neurosci. 2010 Feb;13(2):190-6. doi: 10.1038/nn.2476. Epub 2009 Dec 27.
Excessive synaptic loss is thought to be one of the earliest events in Alzheimer's disease. Amyloid beta (Abeta), a peptide secreted in an activity-modulated manner by neurons, has been implicated in the pathogenesis of Alzheimer's disease by removing dendritic spines, sites of excitatory synaptic transmission. However, issues regarding the subcellular source of Abeta, as well as the mechanisms of its production and actions that lead to synaptic loss, remain poorly understood. In rat organotypic slices, we found that acute overproduction of either axonal or dendritic Abeta reduced spine density and plasticity at nearby ( approximately 5-10 mum) dendrites. The production of Abeta and its effects on spines were sensitive to blockade of action potentials or nicotinic receptors; the effects of Abeta (but not its production) were sensitive to NMDA receptor blockade. Notably, only 30-60 min blockade of Abeta overproduction permitted induction of plasticity. Our results indicate that continuous overproduction of Abeta at dendrites or axons acts locally to reduce the number and plasticity of synapses.
过度的突触损失被认为是阿尔茨海默病的最早事件之一。淀粉样β肽（Abeta）是一种由神经元以活性调节方式分泌的肽，通过去除树突棘（兴奋性突触传递的部位）而被牵连到阿尔茨海默病的发病机制中。然而，关于 Abeta 的亚细胞来源，以及导致突触损失的其产生和作用的机制，仍然知之甚少。在大鼠器官型切片中，我们发现急性过量产生轴突或树突 Abeta 都会降低附近（约 5-10 µm）树突上的棘密度和可塑性。Abeta 的产生及其对棘的作用对动作电位或烟碱型乙酰胆碱受体阻断敏感；Abeta 的作用（而不是其产生）对 NMDA 受体阻断敏感。值得注意的是，只有 30-60 分钟的 Abeta 过量产生阻断才能诱导可塑性。我们的结果表明，树突或轴突上 Abeta 的持续过量产生会局部作用于减少突触的数量和可塑性。
