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J Biol Chem. 2017 May 5;292(18):7327-7337. doi: 10.1074/jbc.M116.761189. Epub 2017 Mar 10.

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

Author information

1
From the Institute of Medical Biochemistry Leopoldo de Meis.
2
Institute of Biophysics Carlos Chagas Filho.
3
Institute of Biomedical Sciences.
4
Division of Neurosurgery and Division of Neurology/Epilepsy Program, Clementino Fraga Filho University Hospital, and.
5
School of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ 21941-902, Brazil and.
6
the Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada.
7
From the Institute of Medical Biochemistry Leopoldo de Meis, ferreira@bioqmed.ufrj.br.

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.

KEYWORDS:

Alzheimer disease; amyloid β (Aβ); amyloid β oligomers; brain; memory; neurexin; neuroligin; neuron; synapse

PMID:
28283575
PMCID:
PMC5418035
DOI:
10.1074/jbc.M116.761189
[Indexed for MEDLINE]
Free PMC Article

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