Regulation of Presynaptic Ca2+, Synaptic Plasticity and Contextual Fear Conditioning by a N-terminal β-Amyloid Fragment
Regulation of Presynaptic Ca2+, Synaptic Plasticity and Contextual Fear Conditioning by a N-terminal β-Amyloid Fragment
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DOI：
10.1523/jneurosci.0326-14.2014
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发表时间：
2014-10-22
影响因子：
5.3
通讯作者：
Nichols, Robert A.
中科院分区：
文献类型：
--
作者：
Lawrence, James L. M.;Tong, Mei;Nichols, Robert A.
可溶性β -淀粉样蛋白已被证明调节突触前Ca2+和突触可塑性。特别是，小摩尔β -淀粉样蛋白被发现对突触前尼古丁受体具有激动剂样作用，并以依赖于尼古丁受体的方式增强长期增强（LTP）。在这里，我们报告了一个功能性的n端结构域存在于β -淀粉样蛋白中，其具有激动剂样活性。该序列对应于由α -分泌酶和β -分泌酶以及常驻羧肽酶共同作用产生的n端片段。n端β -淀粉样蛋白片段存在于健康成年人以及阿尔茨海默病患者的大脑和脑脊液中。与全长β -淀粉样蛋白不同，n端β -淀粉样蛋白片段是单体的，无毒。在使用模型重建的啮齿动物神经母细胞瘤细胞系和分离的小鼠神经末梢的Ca2+成像研究中，n端β -淀粉样蛋白片段在其对尼古丁受体的激动剂样作用方面被证明是高效的，比全长β -淀粉样蛋白片段更有效。此外，n端β -淀粉样蛋白片段增强了θ爆发诱导的破伤风后增强和小鼠海马切片的LTP。n端片段也挽救了被全长β -淀粉样蛋白水平升高抑制的LTP。在双侧海马背侧注射n端β -淀粉样蛋白片段后，情境恐惧条件反射也得到了强烈增强。同时使用烟碱拮抗剂可减弱片段诱导的恐惧条件反射增强。n端β -淀粉样蛋白片段的活性似乎主要存在于假定的金属结合位点YEVHHQ周围的序列中。这些发现表明，n端β -淀粉样蛋白片段可能是一种有效的内源性神经调节剂。
Soluble beta-amyloid has been shown to regulate presynaptic Ca2+ and synaptic plasticity. In particular, picomolar beta-amyloid was found to have an agonist-like action on presynaptic nicotinic receptors and to augment long-term potentiation (LTP) in a manner dependent upon nicotinic receptors. Here, we report that a functional N-terminal domain exists within beta-amyloid for its agonist-like activity. This sequence corresponds to a N-terminal fragment generated by the combined action of alpha- and beta-secretases, and resident carboxypeptidase. The N-terminal beta-amyloid fragment is present in the brains and CSF of healthy adults as well as in Alzheimer's patients. Unlike full-length beta-amyloid, the N-terminal beta-amyloid fragment is monomeric and nontoxic. In Ca2+ imaging studies using a model reconstituted rodent neuroblastoma cell line and isolated mouse nerve terminals, the N-terminal beta-amyloid fragment proved to be highly potent and more effective than full-length beta-amyloid in its agonist-like action on nicotinic receptors. In addition, the N-terminal beta-amyloid fragment augmented theta burst-induced post-tetanic potentiation and LTP in mouse hippocampal slices. The N-terminal fragment also rescued LTP inhibited by elevated levels of full-length beta-amyloid. Contextual fear conditioning was also strongly augmented following bilateral injection of N-terminal beta-amyloid fragment into the dorsal hippocampi of intact mice. The fragment-induced augmentation of fear conditioning was attenuated by coadministration of nicotinic antagonist. The activity of the N-terminal beta-amyloid fragment appears to reside largely in a sequence surrounding a putative metal binding site, YEVHHQ. These findings suggest that the N-terminal beta-amyloid fragment may serve as a potent and effective endogenous neuromodulator.