Amyloid‐β oligomers interact with neurexin and diminish neurexin‐mediated excitatory presynaptic organization
Open accessAbstract
Alzheimer's disease (AD) is characterized by excessive production and deposition of amyloid-beta (Aβ) proteins as well as synapse dysfunction and loss. While soluble Aβ oligomers (AβOs) have deleterious effects on synapse function and reduce synapse number, the underlying molecular mechanisms are not well understood. Here we screened synaptic organizer proteins for cell-surface interaction with AβOs and identified a novel interaction between neurexins (NRXs) and AβOs. AβOs bind to NRXs via the N-terminal histidine-rich domain (HRD) of β-NRX1/2/3 and alternatively-spliced inserts at splicing site 4 of NRX1/2. In artificial synapse-formation assays, AβOs diminish excitatory presynaptic differentiation induced by NRX-interacting proteins including neuroligin1/2 (NLG1/2) and the leucine-rich repeat transmembrane protein LRRTM2. Although AβOs do not interfere with the binding of NRX1β to NLG1 or LRRTM2, time-lapse imaging revealed that AβO treatment reduces surface expression of NRX1β on axons and that this reduction depends on the NRX1β HRD. In transgenic mice expressing mutated human amyloid precursor protein, synaptic expression of β-NRXs, but not α-NRXs, decreases. Thus our data indicate that AβOs interact with NRXs and that this interaction inhibits NRX-mediated presynaptic differentiation by reducing surface expression of axonal β-NRXs, providing molecular and mechanistic insights into how AβOs lead to synaptic pathology 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 [57]
The Discussion reports that neurexins bind Aβ42 oligomers. It says this interaction reduces neurexin expression on axons and may contribute to synaptic pathology; blocking the interaction is proposed as a possible way to prevent pathology. The cited paper does not establish that neurexins bind APP or mediate APP’s synaptogenic activity. No page numbers are available in our copy. (LLM, conf=0.89)
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- Authors
- Naito, Y., Tanabe, Y., Lee, A. K., Hamel, E., & Takahashi, H.
- Affiliations
- Montreal Clinical Research Institute (CA)
- Corresponding author
- Takahashi, Hideto
- ORCID
- Takahashi, Hideto
- Venue
- Scientific Reports
- Published
- 2017-02-13
- Volume
- 7
- Issue
- 1
- Pages
- 42548-42548
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5304201
- OpenAlex
- W2587921648
- Cited by
- 42
- References
- 61
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 4 · 2023: 5 · 2022: 8 · 2021: 3 · 2020: 1 · 2019: 4 · 2018: 1 · 2017: 3
- FWCI
- 1.82
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Gladstone Institutes
- Scottish Rite Charitable Foundation of Canada
- Alzheimer Society
- University of California, San Francisco
- Alzheimer Society Research Program
- Canadian Institutes of Health Research (MOP- 126001, 133517_1, 126001)
- 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, neurexin, Alzheimer's disease, presynaptic differentiation, synaptic dysfunction, histidine-rich domain, neuroligins, alternative splicing, amyloid precursor protein mutations, synaptic loss
- MeSH terms
- Alzheimer Disease, Animals, Axons, Cell Line, Cells, Cultured, Chlorocebus aethiops, Disease Models, Animal, Humans, Membrane Proteins, Nerve Tissue Proteins, Protein Binding, Cell Adhesion Molecules, Neuronal, Gene Expression, Amyloid beta-Peptides, Alternative Splicing, Presynaptic Terminals, COS Cells, Mice, Protein Interaction Domains and Motifs, Synaptic Potentials, Protein Multimerization
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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