Abramov Efrat, Dolev Iftach, Fogel Hilla, Ciccotosto Giuseppe D, Ruff Eyal, Slutsky Inna
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Nat Neurosci. 2009 Dec;12(12):1567-76. doi: 10.1038/nn.2433.
Accumulation of cerebral amyloid-beta peptide (Abeta) is essential for developing synaptic and cognitive deficits in Alzheimer's disease. However, the physiological functions of Abeta, as well as the primary mechanisms that initiate early Abeta-mediated synaptic dysfunctions, remain largely unknown. Here we examine the acute effects of endogenously released Abeta peptides on synaptic transfer at single presynaptic terminals and synaptic connections in rodent hippocampal cultures and slices. Increasing extracellular Abeta by inhibiting its degradation enhanced release probability, boosting ongoing activity in the hippocampal network. Presynaptic enhancement mediated by Abeta was found to depend on the history of synaptic activation, with lower impact at higher firing rates. Notably, both elevation and reduction in Abeta levels attenuated short-term synaptic facilitation during bursts in excitatory synaptic connections. These observations suggest that endogenous Abeta peptides have a crucial role in activity-dependent regulation of synaptic vesicle release and might point to the primary pathological events that lead to compensatory synapse loss in Alzheimer's disease.
脑淀粉样β肽（Aβ）的积累对于阿尔茨海默病中突触和认知缺陷的发展至关重要。然而，Aβ的生理功能以及引发早期Aβ介导的突触功能障碍的主要机制在很大程度上仍不清楚。在这里，我们研究了内源性释放的Aβ肽对啮齿动物海马培养物和切片中单个突触前终末的突触传递以及突触连接的急性影响。通过抑制其降解来增加细胞外Aβ会提高释放概率，增强海马网络中的持续活动。发现由Aβ介导的突触前增强取决于突触激活的历史，在较高放电频率下影响较小。值得注意的是，Aβ水平的升高和降低都会减弱兴奋性突触连接爆发期间的短期突触易化。这些观察结果表明，内源性Aβ肽在依赖活动的突触小泡释放调节中起关键作用，并且可能指向导致阿尔茨海默病中代偿性突触丧失的主要病理事件。
