Synaptic Organizers in Alzheimer’s Disease: A Classification Based on Amyloid-β Sensitivity
Open accessAbstract
Synaptic pathology is one of the major hallmarks observed from the early stage of Alzheimer's disease (AD), leading to cognitive and memory impairment characteristic of AD patients. Synaptic connectivity and specificity are regulated by multiple trans-bindings between pre- and post-synaptic organizers, the complex of which exerts synaptogenic activity. Neurexins (NRXs) and Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are the major presynaptic organizers promoting synaptogenesis through their distinct binding to a wide array of postsynaptic organizers. Recent studies have shown that amyloid-β oligomers (AβOs), a major detrimental molecule in AD, interact with NRXs and neuroligin-1, an NRX-binding postsynaptic organizer, to cause synaptic impairment. On the other hand, LAR-RPTPs and their postsynaptic binding partners have no interaction with AβOs, and their synaptogenic activity is maintained even in the presence of AβOs. Here, we review the current evidence regarding the involvement of synaptic organizers in AD, with a focus on Aβ synaptic pathology, to propose a new classification where NRX-based and LAR-RPTP-based synaptic organizing complexes are classified into Aβ-sensitive and Aβ-insensitive synaptic organizers, respectively. We further discuss how their different Aβ sensitivity is involved in Aβ vulnerability and tolerance of synapses for exploring potential therapeutic approaches for AD.
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NRXN3 is the isoform most consistently implicated in AD pathogenesis.
“given that this isoform has been most consistently implicated in AD pathogenesis35–39.”
From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [37]
The section “Neurexin: A Novel Binding Partner of Aβ Oligomers” (page unavailable) reports significantly decreased NRXN3 expression in AD patients, supporting an association with AD. But it also says that which neurexin isoforms are mainly affected in AD is not fully understood; it does not establish NRXN3 as the most consistently implicated isoform. (LLM, conf=0.88)
Experimental — accuracy not yet measuredNeurexins have been shown to regulate APP synaptic functions and/or modulate Aβ-induced synaptotoxicity.
“neurexins have been shown to regulate APP synaptic functions and/or modulate Aβ-induced synaptotoxicity36,37,48.”
From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [37]
The section “Neurexin: A Novel Binding Partner of Aβ Oligomers” (page unavailable) reports that Aβ oligomers reduce axonal β-neurexin and impair neurexin-mediated presynaptic assembly, supporting a role in Aβ-induced synaptic dysfunction. The passages do not establish that neurexins regulate APP synaptic functions; the paper instead identifies an APP interaction for LRRTM3. (LLM, conf=0.84)
Experimental — accuracy not yet measured
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“NRXN signaling is of particular interest, as neurexins have been shown to regulate APP synaptic functions and/or modulate Aβ-induced synaptotoxicity 36,37,48 .”
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Ollendorff, M. K., Chofflet, N., Bicer, D., Skeldal, S., Duan, J., Feller, B., Vilstrup, J., Groth, R., Sivagurunathan, S., Dashti, H., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.02.16.638491
Self-citationJoshi, K., Chen, M., & Xuan, Z. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.09.26.678794
Kageyama, Y., 遠山, 育., KAGEYAMA, Y., IRIE, Y., MATSUSHIMA, Y., SEGAWA, T., BELLIER, J.-P., HIDAKA, K., SUGIYAMA, H., KANEDA, D., et al. (2021) · Institutional Repositories DataBase (IRDB)
- Authors
- Lee, A. K., Khaled, H., Chofflet, N., & Takahashi, H.
- Affiliations
- Montreal Clinical Research Institute (CA)
- Corresponding author
- Takahashi, Hideto
- Venue
- Frontiers in Cellular Neuroscience
- Publisher
- Frontiers Media SA
- Published
- 2020-09-02
- Volume
- 14
- Pages
- 281-281
- ISSN
- 1662-5102 (ISSN-L)
- PMC
- PMC7492772
- OpenAlex
- W3082757515
- Cited by
- 14
- References
- 168
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 4 · 2022: 1 · 2021: 3
- FWCI
- 0.26
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Cellular Neuroscience (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Canadian Institutes of Health Research (PTJ-159588)
- Alzheimer Society Research Program (Biomedical Research Grant)
- Natural Sciences and Engineering Research Council of Canada (RGPIN-2017-04753, Doctoral award)
- Fonds de Recherche du Québec - Santé (Senior)
- Institut de Recherche Clinique De Montréal (Emmanuel-Triassi Scholarship)
- 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
- Alzheimer's disease, synaptic organizer, amyloid-beta oligomers, neurexin, neuroligin-1, synaptogenesis, synaptic pathology, therapeutic target
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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