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Interaction of amyloid-? (A?) oligomers with neurexin 2? and neuroligin 1 mediates synapse damage and memory loss in mice.

ABSTRACT: Brain accumulation of the amyloid-? protein (A?) and synapse loss are neuropathological hallmarks of Alzheimer disease (AD). A? oligomers (A?Os) 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 A?Os 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 A?Os with Nrxs or NLs mediates synapse damage and cognitive impairment in AD models. We found that A?Os interact with different isoforms of Nrx and NL, including Nrx2? and NL1. Anti-Nrx2? and anti-NL1 antibodies reduced A?O binding to hippocampal neurons and prevented A?O-induced neuronal oxidative stress and synapse loss. Anti-Nrx2? and anti-NL1 antibodies further blocked memory impairment induced by A?Os in mice. The results indicate that Nrx2? and NL1 are targets of A?Os and that prevention of this interaction reduces the deleterious impact of A?Os on synapses and cognition. Identification of Nrx2? and NL1 as synaptic components that interact with A?Os may pave the way for development of novel approaches aimed at halting synapse failure and cognitive loss in AD.

SUBMITTER: Brito-Moreira J

PROVIDER: S-EPMC5418035 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Interaction of amyloid-β (Aβ) oligomers with neurexin 2α and neuroligin 1 mediates synapse damage and memory loss in mice.

Brito-Moreira Jordano J Lourenco Mychael V MV Oliveira Mauricio M MM Ribeiro Felipe C FC Ledo José Henrique JH Diniz Luan P LP Vital Juliana F S JFS Magdesian Margaret H MH Melo Helen M HM Barros-Aragão Fernanda F de Souza Jorge M JM Alves-Leon Soniza V SV Gomes Flavia C A FCA Clarke Julia R JR Figueiredo Cláudia P CP De Felice Fernanda G FG Ferreira Sergio T ST

The Journal of biological chemistry 20170310 18

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 syna ...[more]

PMID: 28283575

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Project description:BackgroundThe lack of effective treatments for Alzheimer's disease (AD) reflects an incomplete understanding of disease mechanisms. Alterations in proteins involved in mitochondrial dynamics, an essential process for mitochondrial integrity and function, have been reported in AD brains. Impaired mitochondrial dynamics causes mitochondrial dysfunction and has been associated with cognitive impairment in AD. Here, we investigated a possible link between pro-inflammatory interleukin-1 (IL-1), mitochondrial dysfunction, and cognitive impairment in AD models.MethodsWe exposed primary hippocampal cell cultures to amyloid-β oligomers (AβOs) and carried out AβO infusions into the lateral cerebral ventricle of cynomolgus macaques to assess the impact of AβOs on proteins that regulate mitochondrial dynamics. Where indicated, primary cultures were pre-treated with mitochondrial division inhibitor 1 (mdivi-1), or with anakinra, a recombinant interleukin-1 receptor (IL-1R) antagonist used in the treatment of rheumatoid arthritis. Cognitive impairment was investigated in C57BL/6 mice that received an intracerebroventricular (i.c.v.) infusion of AβOs in the presence or absence of mdivi-1. To assess the role of interleukin-1 beta (IL-1β) in AβO-induced alterations in mitochondrial proteins and memory impairment, interleukin receptor-1 knockout (Il1r1-/-) mice received an i.c.v. infusion of AβOs.ResultsWe report that anakinra prevented AβO-induced alteration in mitochondrial dynamics proteins in primary hippocampal cultures. Altered levels of proteins involved in mitochondrial fusion and fission were observed in the brains of cynomolgus macaques that received i.c.v. infusions of AβOs. The mitochondrial fission inhibitor, mdivi-1, alleviated synapse loss and cognitive impairment induced by AβOs in mice. In addition, AβOs failed to cause alterations in expression of mitochondrial dynamics proteins or memory impairment in Il1r1-/- mice.ConclusionThese findings indicate that IL-1β mediates the impact of AβOs on proteins involved in mitochondrial dynamics and that strategies aimed to prevent pathological alterations in those proteins may counteract synapse loss and cognitive impairment in AD.

Dataset Information

Interaction of amyloid-? (A?) oligomers with neurexin 2? and neuroligin 1 mediates synapse damage and memory loss in mice.

Publications

Interaction of amyloid-β (Aβ) oligomers with neurexin 2α and neuroligin 1 mediates synapse damage and memory loss in mice.

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