Mossy fiber long-term potentiation deficits in BACE1 knock-outs can be rescued by activation of alpha7 nicotinic acetylcholine receptors.
Mossy fiber long-term potentiation deficits in BACE1 knock-outs can be rescued by activation of alpha7 nicotinic acetylcholine receptors.
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DOI：
10.1523/jneurosci.1070-10.2010
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发表时间：
2010-10-13
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;Lee A;Laird F;Wong PC;Lee HK
β-位点淀粉样前体蛋白裂解酶1(BACE1)是一种神经元β分泌酶，负责产生β-淀粉样多肽(A-β)，是阿尔茨海默病(AD)的关键治疗靶点之一。尽管完全去除BACE1基因可以阻止Aβ的形成，但我们报告了BACE1基因敲除小鼠在海马区苔藓纤维(MF)到CA3突触的严重突触前缺陷，这是BACE1表达的主要部位。我们还发现，这些缺陷可能是由于突触前钙调节异常所致。胆碱能系统与AD有关，在某些情况下涉及钙离子通透性α7-烟碱型乙酰胆碱受体(NAChRs)。在这里，我们报道了通过α7-nAChRs短暂应用尼古丁可以恢复BACE1基因敲除的苔藓纤维LTP(MfLTP)。我们的数据表明，激活α7-nAChRs可以恢复BACE1基因敲除中的突触前缺陷。
Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1)–the neuronal β-secretase responsible for producing β-amyloid (Aβ) peptides–emerged as one of the key therapeutic targets of Alzheimer's disease (AD). Although complete ablation of the BACE1 gene prevents Aβ formation, we reported that BACE1 knockout mice display severe presynaptic deficits at mossy fiber (MF) to CA3 synapses in the hippocampus, a major locus of BACE1 expression. We also found that the deficits are likely due to abnormal presynaptic Ca2+ regulation. Cholinergic system has been implicated in AD, in some cases involving Ca2+-permeable α7-nicotinic acetylcholine receptors (nAChRs). Here we report that brief application of nicotine, via α7-nAChRs, can restore mossy fiber LTP (mfLTP) in BACE1 knockouts. Our data suggest that activating α7-nAChRs can recover the presynaptic deficits in BACE1 knockouts.