The secreted Wnt antagonist Dickkopf-1 is required for amyloid β-mediated synaptic loss
Open accessAbstract
Extensive evidence supports a central role for amyloid-β (Aβ) in the pathogenesis of Alzheimer's disease (AD). Synaptic loss mediated by Aβ in early stages of the disease might contribute to cognitive impairments. However, little is known about the mechanism by which Aβ induces the loss of synapses. The expression of the Wnt antagonist Dickkopf-1 (Dkk1) is increased in brains of AD patients and in AD transgenic mouse models, suggesting that dysfunction of Wnt signaling could contribute to AD pathology. Here we report that acute exposure to Aβ oligomers induces Dkk1 expression together with the loss of synaptic sites. Importantly, Dkk1-neutralizing antibodies suppress Aβ-induced synapse loss in mouse brain slices. In mature rat hippocampal neurons, Dkk1 decreases the number of synapses without affecting cell viability. Ultrastructural analyses revealed that Wnt blockade decreases the size of presynaptic and postsynaptic terminals. Time-lapse recordings of RFP-labeled stable synaptic sites demonstrate that Dkk1 induces the dispersal of synaptic components. These findings identify Dkk1 as a potential therapeutic target for the treatment of AD.
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Tau phosphorylation results in enhanced dendritic fyn localization coupled to a disruption of the PSD-95/NMDAR interaction and abnormal postsynaptic density ultrastructure.
“This tau phosphorylation results in enhanced dendritic fyn localization coupled to a disruption of the PSD-95/NMDAR interaction (Mondragon-Rodriguez et al., 2012) and abnormal postsynaptic density ultrastructure (Purro et al., 2012).”
From Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau−/− mice (2017) · cites this paper as Purro et al., 2012
The section “Dkk1 reduces the size of synapses in mature neurons” (Fig. 3E–F; page not provided) reports electron-microscopy evidence of reduced postsynaptic-density length and area, supporting the cited ultrastructural finding. But it attributes those changes to Dkk1 treatment, not tau phosphorylation; the sentence’s causal link to tau is not supported by this paper. The Fyn and PSD-95/NMDAR portion is attached to a different citation. (LLM, conf=0.86)
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Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau−/− mice
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- Authors
- Purro, S. A., Dickins, E. M., & Salinas, P. C.
- Affiliations
- University College London (GB)
- Corresponding author
- Salinas, Patricia C.
- ORCID
- Salinas, Patricia C.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-03-07
- Volume
- 32
- Issue
- 10
- Pages
- 3492-3498
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6621056
- OpenAlex
- W1963836337
- Cited by
- 195
- References
- 4
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 10 · 2023: 19 · 2022: 9 · 2021: 13 · 2020: 15 · 2019: 20 · 2018: 17 · 2017: 12 · 2016: 9 · 2015: 9 · 2014: 20 · 2013: 16 · 2012: 4
- FWCI
- 9.86
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust
- European Commission
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council
- 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
- DKK1, amyloid-beta, synaptic loss, Alzheimer's disease, Wnt signaling, amyloid-beta oligomers, hippocampal neurons, presynaptic terminals, postsynaptic terminals, synaptic ultrastructure, therapeutic target
- MeSH terms
- Animals, Female, Hippocampus, Male, Synapses, Up-Regulation, Amyloid beta-Peptides, Intercellular Signaling Peptides and Proteins, Mice, Rats, Wnt Signaling Pathway
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