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首页> 外文期刊>Current Biology: CB >Drosophila Full-Length Amyloid Precursor Protein Is Required for Visual Working Memory and Prevents Age-Related Memory Impairment
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Drosophila Full-Length Amyloid Precursor Protein Is Required for Visual Working Memory and Prevents Age-Related Memory Impairment

机译：可视化工作记忆需要果蝇全长淀粉样蛋白前体蛋白，并防止年龄相关的记忆障碍

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The beta-amyloid precursor protein (APP) plays a central role in the etiology of Alzheimer's disease (AD). However, its normal physiological functions are still unclear. APP is cleaved by various secretases whereby sequential processing by the beta- and gamma-secretases produces the beta-amyloid peptide that is accumulating in plaques that typify AD. In addition, this produces secreted N-terminal sAPP beta fragments and the APP intracellular domain (AICD). Alternative cleavage by alpha-secretase results in slightly longer secreted sAPP alpha fragments and the identical AICD. Whereas the AICD has been connected with transcriptional regulation, sAPPa fragments have been suggested to have a neurotrophic and neuroprotective role [1]. Moreover, expression of sAPP alpha in APP-deficient mice could rescue their deficits in learning, spatial memory, and long-term potentiation [2]. Loss of the Drosophila APP-like (APPL) protein impairs associative olfactory memory formation and middle-term memory that can be rescued with a secreted APPL fragment [3]. We now show that APPL is also essential for visual working memory. Interestingly, this short-term memory declines rapidly with age, and this is accompanied by enhanced processing of APPL in aged flies. Furthermore, reducing secretase-mediated proteolytic processing of APPL can prevent the age-related memory loss, whereas overexpression of the secretases aggravates the aging effect. Rescue experiments confirmed that this memory requires signaling of full-length APPL and that APPL negatively regulates the neuronal-adhesion molecule Fasciclin 2. Overexpression of APPL or one of its secreted N termini results in a dominant-negative interaction with the FASII receptor. Therefore, our results show that specific memory processes require distinct APPL products.
机译：β-淀粉样蛋白前体蛋白（APP）在阿尔茨海默病的病因（AD）中起着核心作用。然而，其正常的生理功能仍然不清楚。应用通过各种分泌酶切割，由此β-和γ分泌酶顺序处理产生β-淀粉样肽，其在典型的斑块中积聚。此外，这产生分泌的N-末端SAPPβ片段和APP细胞内结构域（AICD）。 α-分泌酶的替代裂解导致分泌的SAPPα片段稍长，并且相同的AICD。虽然AICD已与转录调节相关联，但已经提出了萨普布片段具有神经营养和神经保护作用[1]。此外，APP缺陷小鼠中SAPPα的表达可以拯救他们在学习，空间记忆和长期增强方面的缺陷[2]。衰落的果蝇APP样（Appl）蛋白质损害可联想的嗅觉记忆形成和中期记忆，可以用分泌的苹果片段救出[3]。我们现在显示应用程序对于可视化工作记忆也是必不可少的。有趣的是，这种短期记忆随着年龄的增长而迅速下降，这伴随着苹果苍蝇的增强处理。此外，减少苹果苷介导的苹果苷蛋白水解加工可以预防年龄相关的记忆损失，而分泌凝集的过度表达会加剧老化效果。救援实验证实，该记忆需要全长App的信号传导，并且该申请对神经元 - 粘合分子Fasciclin 2进行负面调节。苹果或其分泌的N Termini的过表达导致与FasII受体的显性负相互作用。因此，我们的结果表明，特定的内存流程需要不同的苹果产品。

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  • 来源
    《Current Biology: CB》 |2018年第5期|共10页
  • 作者

    Rieche Franziska; Carmine-Simmen Katia; Poeck Burkhard; Kretzschmar Doris; Strauss Roland;

  • 作者单位

    Johannes Gutenberg Univ Mainz Inst Entwicklungsbiol &

    Neurobiol Colonel Kleinmann Weg 2 D-55099 Mainz Germany;

    Oregon Inst Occupat Hlth Sci 3181 SW Sam Jackson Pk Rd Portland OR 97201 USA;

    Johannes Gutenberg Univ Mainz Inst Entwicklungsbiol &

    Neurobiol Colonel Kleinmann Weg 2 D-55099 Mainz Germany;

    Oregon Inst Occupat Hlth Sci 3181 SW Sam Jackson Pk Rd Portland OR 97201 USA;

    Johannes Gutenberg Univ Mainz Inst Entwicklungsbiol &

    Neurobiol Colonel Kleinmann Weg 2 D-55099 Mainz Germany;

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  • 正文语种 eng
  • 中图分类 生物科学;
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