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

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...

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Bibliographic Details
Published in:The Journal of biological chemistry 2017-05, Vol.292 (18), p.7327-7337
Main Authors: 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.
Format: Article
Language:English
Subjects:
Alzheimer disease
Alzheimer Disease - genetics
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Amyloid beta-Peptides - genetics
Amyloid beta-Peptides - metabolism
amyloid β (Aβ)
amyloid β oligomers
Animals
brain
Brain - metabolism
Brain - pathology
Cell Adhesion Molecules, Neuronal - genetics
Cell Adhesion Molecules, Neuronal - metabolism
Cells, Cultured
Disease Models, Animal
Humans
Male
memory
Mice
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
neurexin
Neurobiology
neuroligin
neuron
Peptide Fragments - genetics
Peptide Fragments - metabolism
Protein Aggregation, Pathological - genetics
Protein Aggregation, Pathological - metabolism
Protein Aggregation, Pathological - pathology
Rats
Rats, Wistar
synapse
Synapses - genetics
Synapses - metabolism
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M116.761189