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Nature:被忽视了30年!老年痴呆的关键肽类

来源:生物谷 2015-09-08 11:01

2015年9月8日 讯 /生物谷BIOON/ --近日,发表于国际杂志Nature上的一项研究论文中,来自德国慕尼黑大学(Ludwig Maximilian University of Munich)的研究人员通过研究鉴别出了一种新型肽类,其在阿尔兹海默氏症发病过程中扮演着重要角色,研究者发现此前被忽视的eta-淀粉样蛋白可以干扰神经元的功能而且可以中和β-淀粉样蛋白,该研究对于其临床试验或可带来一定帮助。

阿尔兹海默氏症主要表现为大脑多个区域中特殊的神经毒性蛋白质的累积,对这些不溶性累积蛋白的化学分析揭示其是由短蛋白片段家族组成,其被称为β-淀粉样蛋白肽,由一种名为APP的前体蛋白衍生而成;研究者在文章中阐明了阿尔兹海默氏症的发病机理,这对于理解该疾病的发病原因及开发新型疗法提供了一定基础,研究者指出,APP第二种分裂模式的存在可以参与一些未知的分裂过程,并且会产生一种替代的肽类。

研究者将这种eta-淀粉样蛋白命名为“淀粉样蛋白-η”,该蛋白的产生过程被忽略了大约30年,这是因为研究者将注意力集中于阐明阿尔兹海默氏症患者大脑中β-淀粉样蛋白的来源,以及以该β-淀粉样蛋白为基础开发抑制疾病发展的新策略。

随后研究人员检测了eta-淀粉样蛋白对大脑中神经细胞功能的效应,我们都知道β-淀粉样蛋白可以促进神经细胞活性过强,而如今研究者发现eta-淀粉样蛋白可以抵御对抗这种活性增强的效应。

相关研究发现对于后期进行人类临床试验靶向作用β-淀粉样蛋白具有一定的意义,比如研究人员可以设计出具有药理学抑制作用的β-分泌酶类,这种蛋白水解酶可以释放毒性的β-淀粉样蛋白,从而减少阿尔兹海默氏症患者的记忆缺失;研究者指出,阻断β-分泌酶的活性或可降低β-淀粉样蛋白的水平,然而这同时会大量增加eta-淀粉样蛋白的产生,最终导致神经元活性的减弱以及大脑功能的中和;研究者后期还需要进行更多研究来解释这种新型肽类对阿尔兹海默氏症的作用。(生物谷Bioon.com)

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η-Secretase processing of APP inhibits neuronal activity in the hippocampus

Michael Willem, Sabina Tahirovic, Marc Aurel Busche, Saak V. Ovsepian, Magda Chafai, Scherazad Kootar, Daniel Hornburg, Lewis D. B. Evans, Steven Moore, Anna Daria, Heike Hampel, Veronika Müller, Camilla Giudici, Brigitte Nuscher, Andrea Wenninger-Weinzierl, Elisabeth Kremmer, Michael T. Heneka, Dietmar R. Thal, Vilmantas Giedraitis, Lars Lannfelt, Ulrike Müller, Frederick J. Livesey, Felix Meissner, Jochen Herms, Arthur Konnerth et al.

Alzheimer disease (AD) is characterized by the accumulation of amyloid plaques, which are predominantly composed of amyloid-β peptide1. Two principal physiological pathways either prevent or promote amyloid-β generation from its precursor, β-amyloid precursor protein (APP), in a competitive manner1. Although APP processing has been studied in great detail, unknown proteolytic events seem to hinder stoichiometric analyses of APP metabolism in vivo2. Here we describe a new physiological APP processing pathway, which generates proteolytic fragments capable of inhibiting neuronal activity within the hippocampus. We identify higher molecular mass carboxy-terminal fragments (CTFs) of APP, termed CTF-η, in addition to the long-known CTF-α and CTF-β fragments generated by the α- and β-secretases ADAM10 (a disintegrin and metalloproteinase 10) and BACE1 (β-site APP cleaving enzyme 1), respectively. CTF-η generation is mediated in part by membrane-bound matrix metalloproteinases such as MT5-MMP, referred to as η-secretase activity. η-Secretase cleavage occurs primarily at amino acids 504–505 of APP695, releasing a truncated ectodomain. After shedding of this ectodomain, CTF-η is further processed by ADAM10 and BACE1 to release long and short Aη peptides (termed Aη-α and Aη-β). CTFs produced by η-secretase are enriched in dystrophic neurites in an AD mouse model and in human AD brains. Genetic and pharmacological inhibition of BACE1 activity results in robust accumulation of CTF-η and Aη-α. In mice treated with a potent BACE1 inhibitor, hippocampal long-term potentiation was reduced. Notably, when recombinant or synthetic Aη-α was applied on hippocampal slices ex vivo, long-term potentiation was lowered. Furthermore, in vivo single-cell two-photon calcium imaging showed that hippocampal neuronal activity was attenuated by Aη-α. These findings not only demonstrate a major functionally relevant APP processing pathway, but may also indicate potential translational relevance for therapeutic strategies targeting APP processing.

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