APP processing and synaptic function
APP processing and synaptic function
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DOI：
10.1016/s0896-6273(03)00124-7
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发表时间：
2003-03-27
期刊：
影响因子：
16.2
通讯作者：
Malinow, R
中科院分区：
文献类型：
--
作者：
Kamenetz, F;Tomita, T;Malinow, R
大量证据表明，A β肽和淀粉样前体蛋白（APP）的其他衍生物是阿尔茨海默病（AD）发病机制的核心。然而，APP及其蛋白水解衍生物与神经元电生理学的功能关系尚不清楚。在这里，我们表明，神经元的活动调节的形成和分泌的Abeta肽在海马切片神经元过表达APP。反过来，Abeta选择性地抑制兴奋性突触传递到神经元过表达APP，以及附近的神经元不。这种抑制依赖于NMDA-R活性，并且可以通过阻断神经元活性来逆转。过量Abeta引起的突触抑制可能导致早期AD期间的认知下降。此外，我们提出，内源性Abeta产生的活动依赖性调制可能通常参与负反馈，可以保持神经元的过度活跃。这种反馈系统的破坏可能有助于AD的疾病进展。
A large body of evidence has implicated Abeta peptides and other derivatives of the amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease (AD). However, the functional relationship of APP and its proteolytic derivatives to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons that overexpress APP, as well as nearby neurons that do not. This depression depends on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic depression from excessive Abeta could contribute to cognitive decline during early AD. In addition, we propose that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in AD.