title: Interaction of amyloid-β (Aβ) oligomers with neurexin 2α and neuroligin 1 mediates synapse damage and memory loss in mice.
abstract: 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.
authors.affiliation: From the Institute of Medical Biochemistry Leopoldo de Meis.
authors.forename: Jordano
authors.initials: J
authors.lastname: Brito-Moreira
authors.affiliation: From the Institute of Medical Biochemistry Leopoldo de Meis.|Institute of Biophysics Carlos Chagas Filho.
authors.forename: Mychael V
authors.initials: MV
authors.lastname: Lourenco
authors.affiliation: From the Institute of Medical Biochemistry Leopoldo de Meis.|Institute of Biophysics Carlos Chagas Filho.
authors.forename: Mauricio M
authors.initials: MM
authors.lastname: Oliveira
authors.affiliation: From the Institute of Medical Biochemistry Leopoldo de Meis.|Institute of Biophysics Carlos Chagas Filho.
authors.forename: Felipe C
authors.initials: FC
authors.lastname: Ribeiro
authors.affiliation: From the Institute of Medical Biochemistry Leopoldo de Meis.
authors.forename: José Henrique
authors.initials: JH
authors.lastname: Ledo
authors.affiliation: Institute of Biomedical Sciences.
authors.forename: Luan P
authors.initials: LP
authors.lastname: Diniz
authors.affiliation: From the Institute of Medical Biochemistry Leopoldo de Meis.
authors.forename: Juliana F S
authors.initials: JFS
authors.lastname: Vital
authors.affiliation: From the Institute of Medical Biochemistry Leopoldo de Meis.
authors.forename: Margaret H
authors.initials: MH
authors.lastname: Magdesian
authors.affiliation: From the Institute of Medical Biochemistry Leopoldo de Meis.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Melo
authors.affiliation: Institute of Biomedical Sciences.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Barros-Aragão
authors.affiliation: Division of Neurosurgery and Division of Neurology/Epilepsy Program, Clementino Fraga Filho University Hospital, and.
authors.forename: Jorge M
authors.initials: JM
authors.lastname: de Souza
authors.affiliation: Division of Neurosurgery and Division of Neurology/Epilepsy Program, Clementino Fraga Filho University Hospital, and.
authors.forename: Soniza V
authors.initials: SV
authors.lastname: Alves-Leon
authors.affiliation: Institute of Biomedical Sciences.
authors.forename: Flavia C A
authors.initials: FCA
authors.lastname: Gomes
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil and.
authors.forename: Julia R
authors.initials: JR
authors.lastname: Clarke
authors.affiliation: School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil and.
authors.forename: Cláudia P
authors.initials: CP
authors.lastname: Figueiredo
authors.affiliation: From the Institute of Medical Biochemistry Leopoldo de Meis.|the Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
authors.forename: Fernanda G
authors.initials: FG
authors.lastname: De Felice
authors.affiliation: From the Institute of Medical Biochemistry Leopoldo de Meis, ferreira@bioqmed.ufrj.br.|Institute of Biophysics Carlos Chagas Filho.
authors.forename: Sergio T
authors.initials: ST
authors.lastname: Ferreira
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D015816:Cell Adhesion Molecules, Neuronal; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C093175:neurexin II; C093438:neuroligin 1
keywords: Alzheimer disease; amyloid β (Aβ); amyloid β oligomers; brain; memory; neurexin; neuroligin; neuron; synapse