Interaction of amyloid‐β (Aβ) oligomers with neurexin 2α and neuroligin 1 mediates synapse damage and memory loss in mice
Open accessAbstract
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.
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Neurexins can bind to Aβ and APP, thereby preventing Aβ-induced synaptic pathology and mediating the synaptogenic activity of APP.
“In addition, neurexins can bind to Aβ and amyloid precursor protein (APP), thereby preventing Aβ‐induced synaptic pathology and mediating the synaptogenic activity of APP. 56 , 57 , 58”
From Deletion of neuronal <i>Idol</i> ameliorates Alzheimer's disease–related pathologies via APOE receptors (2025) · cites this paper as [58]
The Discussion (page not provided) reports that Aβ oligomers bind neurexins, but says this interaction may contribute to synapse damage. The paper attributes prevention of Aβ-induced synapse loss to antibodies that block the interaction, not to neurexin binding itself. The passages do not establish neurexin binding to APP or mediation of APP’s synaptogenic activity. (LLM, conf=0.88)
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References 64 · Cited by 84
Research works printed but not linked: 2
- Nam, C. I., and Chen, L. (2005) Postsynaptic assembly induced by neur- exin-neuroligin interaction and neurotransmitter. Proc. Natl. Acad. Sci.
- Vitolo, O. V., Sant'Angelo, A., Costanzo, V., Battaglia, F., Arancio, O., and Shelanski, M. (2002) Amyloid -peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc. Natl. Acad. Sci. U.S.A. 99, 13217-13221
- Authors
- Brito-Moreira, J., Lourenco, M. V., Oliveira, M. M., Ribeiro, F. C., Ledo, J. H., Diniz, L. P., Vital, J. F. S., Magdesian, M. H., Melo, H. M., Barros-Aragão, F., de Souza, J. M., Alves-Leon, S. V., Gomes, F. C. A., Clarke, J. R., Figueiredo, C. P., De Felice, F. G., & Ferreira, S. T.
- Affiliations
- Instituto de Biofísica Carlos Chagas Filho (BR)
- Universidade Federal do Rio de Janeiro (BR)
- Corresponding author
- Ferreira, Sergio T.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 292
- Issue
- 18
- Pages
- 7327-7337
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC5418035
- OpenAlex
- W2593993808
- Cited by
- 84
- References
- 64
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 4 · 2023: 7 · 2022: 7 · 2021: 14 · 2020: 11 · 2019: 14 · 2018: 8 · 2017: 6
- FWCI
- 7.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Human Frontier Science Program
- Instituto Nacional de Ciência e Tecnologia de Neurociência Translacional
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta oligomers, neuroligin-1, Alzheimer's disease, synaptic loss, memory impairment, synaptotoxicity, oxidative stress, hippocampal neurons, cognitive impairment
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cells, Cultured, Disease Models, Animal, Humans, Male, Nerve Tissue Proteins, Peptide Fragments, Synapses, Cell Adhesion Molecules, Neuronal, Amyloid beta-Peptides, Rats, Wistar, Mice, Rats, Protein Aggregation, Pathological
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