BACE1 knock-outs display deficits in activity-dependent potentiation of synaptic transmission at mossy fiber to CA3 synapses in the hippocampus.
BACE1 knock-outs display deficits in activity-dependent potentiation of synaptic transmission at mossy fiber to CA3 synapses in the hippocampus.
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DOI：
10.1523/jneurosci.2440-08.2008
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发表时间：
2008-08-27
期刊：
影响因子：
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通讯作者：
Lee HK
中科院分区：
文献类型：
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作者：
Wang H;Song L;Laird F;Wong PC;Lee HK
β-淀粉样蛋白前体蛋白切割酶1 （BACE1）已被确定为一种主要的神经元β分泌酶，对β-淀粉样蛋白（a β）肽的形成至关重要，β-淀粉样蛋白（a β）肽被认为与阿尔茨海默病（AD）的病理有关。因此，BACE1是能够阻止AD进展的关键治疗靶点之一。先前的研究表明，敲除BACE1基因可以阻止Aβ的形成，但会导致CA1突触侧侧Schaffer突触的行为缺陷和特异性突触功能障碍。而BACE1蛋白在CA3苔藓纤维突起处的表达量最高。在这里，我们报告BACE1敲除小鼠显示突触前功能降低，通过增加配对脉冲促进比来测量。更引人注目的是，通常通过突触前释放增加表达的苔藓纤维LTP在敲除中被消除了。虽然在BACE1基因敲除中LTD略大，但它不能逆转。苔藓纤维LTP的特异性缺陷位于cAMP信号的上游，可以通过短暂提高细胞外Ca2+浓度来“拯救”。这些结果表明，BACE1可能在调节苔藓纤维突触的突触前功能，特别是突触前释放的活动依赖性增强中发挥关键作用。
Beta-amyloid precursor protein cleavage enzyme 1 (BACE1) has been identified as a major neuronal β-secretase critical for the formation of β-amyloid (Aβ) peptide, which is thought responsible for the pathology of Alzheimer’s disease (AD). Therefore, BACE1 is one of the key therapeutic targets that can prevent the progression of AD. Previous studies showed that knocking out the BACE1 gene prevents Aβ formation, but results in behavioral deficits and specific synaptic dysfunctions at Schaffer collateral to CA1 synapses. However, BACE1 protein is most highly expressed at the mossy fiber projections in CA3. Here we report that BACE1 knockout mice display reduced presynaptic function, as measured by an increase in paired-pulse facilitation ratio. More dramatically, mossy fiber LTP, which is normally expressed via an increase in presynaptic release, was eliminated in the knockouts. While LTD was slightly larger in the BACE1 knockouts, it could not be reversed. The specific deficit in mossy fiber LTP was upstream of cAMP signaling, and could be “rescued” by transiently elevating extracellular Ca2+ concentration. These results suggest that BACE1 may play a critical role in regulating presynaptic function, especially activity-dependent strengthening of presynaptic release, at mossy fiber synapses.