Turrel Oriane, Goguel Valérie, Preat Thomas
Genes and Dynamics of Memory Systems, Brain Plasticity Unit, Centre National de la Recherche Scientifique, ESPCI Paris, PSL Research University, 75005 Paris, France.
Genes and Dynamics of Memory Systems, Brain Plasticity Unit, Centre National de la Recherche Scientifique, ESPCI Paris, PSL Research University, 75005 Paris, France
J Neurosci. 2017 Oct 25;37(43):10334-10345. doi: 10.1523/JNEUROSCI.1634-17.2017. Epub 2017 Sep 20.
Neprilysins are Type II metalloproteinases known to degrade and inactivate a number of small peptides, in particular the mammalian amyloid-β peptide (Aβ). In , several neprilysins expressed in the brain are required for middle-term (MTM) and long-term memory (LTM) in the dorsal paired medial (DPM) neurons, a pair of large neurons that broadly innervate the mushroom bodies (MB), the center of olfactory memory. These data indicate that one or several peptides need to be degraded for MTM and LTM. We have previously shown that the fly amyloid precursor protein (APPL) is required for memory in the MB. We show here that APPL is also required in adult DPM neurons for MTM and LTM formation. This finding prompted us to search for an interaction between neprilysins and Aβ (dAβ), a cleavage product of APPL. To find out whether dAβ was a neprilysin's target, we used inducible drivers to modulate neprilysin 1 (Nep1) and dAβ expression in adult DPM neurons. Experiments were conducted either in both sexes or in females. We show that Nep1 inhibition makes dAβ expression detrimental to both MTM and LTM. Conversely, memory deficits displayed by dAβ-expressing flies are rescued by Nep1 overexpression. Consistent with behavioral data, biochemical analyses confirmed that Nep1 degrades dAβ. Together, our findings establish that Nep1 and dAβ expressed in DPM neurons are functionally linked for memory processes, suggesting that dAβ is a physiological target for Nep1. Neprilysins are endopeptidases known to degrade a number of small peptides and in particular the amyloid peptide. We previously showed that all four neprilysins expressed in the brain are involved in specific phases of olfactory memory. Here we show that an increase in the level of the neprilysin 1 peptidase overcomes memory deficits induced by amyloid peptide in young flies. Together, the data reveal a functional interaction between neprilysin 1 and amyloid peptide, suggesting that neprilysin 1 degrades amyloid peptide. These findings raise the possibility that, under nonpathological conditions, mammalian neprilysins degrade amyloid peptide to ensure memory formation.
中性内肽酶属于II型金属蛋白酶，已知其可降解并使多种小肽失活，尤其是哺乳动物的β淀粉样肽（Aβ）。在[具体研究中]，大脑中表达的几种中性内肽酶对于背侧配对内侧（DPM）神经元的中期记忆（MTM）和长期记忆（LTM）是必需的，DPM神经元是一对广泛支配蘑菇体（MB）（嗅觉记忆中心）的大神经元。这些数据表明，MTM和LTM需要降解一种或几种肽。我们之前已经表明，果蝇淀粉样前体蛋白（APPL）对于MB中的记忆是必需的。我们在此表明，APPL在成年DPM神经元中对于MTM和LTM的形成也是必需的。这一发现促使我们去寻找中性内肽酶与APPL的裂解产物Aβ（dAβ）之间的相互作用。为了弄清楚dAβ是否是中性内肽酶的作用靶点，我们使用诱导型驱动子来调节成年DPM神经元中中性内肽酶1（Nep1）和dAβ的表达。实验在雌雄两性或仅在雌性中进行。我们表明，抑制Nep1会使dAβ的表达对MTM和LTM均产生有害影响。相反，过表达Nep1可挽救表达dAβ的果蝇所表现出的记忆缺陷。与行为学数据一致，生化分析证实Nep1可降解dAβ。总之，我们的研究结果表明，DPM神经元中表达的Nep1和dAβ在记忆过程中存在功能联系，这表明dAβ是Nep1的生理作用靶点。中性内肽酶是已知可降解多种小肽尤其是淀粉样肽的内肽酶。我们之前表明，大脑中表达的所有四种中性内肽酶都参与嗅觉记忆的特定阶段。在此我们表明，中性内肽酶1肽酶水平的升高可克服年轻果蝇中由淀粉样肽诱导的记忆缺陷。总之，这些数据揭示了中性内肽酶1与淀粉样肽之间的功能相互作用，表明中性内肽酶1可降解淀粉样肽。这些发现增加了一种可能性，即在非病理条件下，哺乳动物的中性内肽酶可降解淀粉样肽以确保记忆形成。
