Brito-Moreira Jordano, Lourenco Mychael V, Oliveira Mauricio M, Ribeiro Felipe C, Ledo José Henrique, Diniz Luan P, Vital Juliana F S, Magdesian Margaret H, Melo Helen M, Barros-Aragão Fernanda, de Souza Jorge M, Alves-Leon Soniza V, Gomes Flavia C A, Clarke Julia R, Figueiredo Cláudia P, De Felice Fernanda G, Ferreira Sergio T
From the Institute of Medical Biochemistry Leopoldo de Meis.
Institute of Biophysics Carlos Chagas Filho.
J Biol Chem. 2017 May 5;292(18):7327-7337. doi: 10.1074/jbc.M116.761189. Epub 2017 Mar 10.
Brain accumulation of the amyloid-β protein (Aβ) and synapse loss are neuropathological hallmarks of Alzheimer disease (AD). Aβ oligomers (AβOs) are synaptotoxins that build up in the brains of patients and are thought to contribute to memory impairment in AD. Thus, identification of novel synaptic components that are targeted by AβOs may contribute to the elucidation of disease-relevant mechanisms. Trans-synaptic interactions between neurexins (Nrxs) and neuroligins (NLs) are essential for synapse structure, stability, and function, and reduced NL levels have been associated recently with AD. Here we investigated whether the interaction of AβOs with Nrxs or NLs mediates synapse damage and cognitive impairment in AD models. We found that AβOs interact with different isoforms of Nrx and NL, including Nrx2α and NL1. Anti-Nrx2α and anti-NL1 antibodies reduced AβO binding to hippocampal neurons and prevented AβO-induced neuronal oxidative stress and synapse loss. Anti-Nrx2α and anti-NL1 antibodies further blocked memory impairment induced by AβOs in mice. The results indicate that Nrx2α and NL1 are targets of AβOs and that prevention of this interaction reduces the deleterious impact of AβOs on synapses and cognition. Identification of Nrx2α and NL1 as synaptic components that interact with AβOs may pave the way for development of novel approaches aimed at halting synapse failure and cognitive loss in AD.
淀粉样β蛋白（Aβ）在大脑中的积累和突触丧失是阿尔茨海默病（AD）的神经病理学特征。Aβ寡聚体（AβOs）是在患者大脑中积累的突触毒素，被认为与AD的记忆损害有关。因此，鉴定AβOs靶向的新型突触成分可能有助于阐明疾病相关机制。神经连接蛋白（Nrxs）和神经配体（NLs）之间的跨突触相互作用对于突触结构、稳定性和功能至关重要，最近已发现NL水平降低与AD有关。在这里，我们研究了AβOs与Nrxs或NLs的相互作用是否介导AD模型中的突触损伤和认知障碍。我们发现AβOs与Nrx和NL的不同异构体相互作用，包括Nrx2α和NL1。抗Nrx2α和抗NL1抗体减少了AβO与海马神经元的结合，并防止了AβO诱导的神经元氧化应激和突触丧失。抗Nrx2α和抗NL1抗体进一步阻断了AβOs在小鼠中诱导的记忆损害。结果表明，Nrx2α和NL1是AβOs的靶点，阻止这种相互作用可降低AβOs对突触和认知的有害影响。将Nrx2α和NL1鉴定为与AβOs相互作用的突触成分，可能为开发旨在阻止AD中突触功能障碍和认知丧失的新方法铺平道路。
