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Fyn inhibition rescues established memory and synapse loss in Alzheimer mice
Open accessAbstract
Objective: Currently no effective disease‐modifying agents exist for the treatment of Alzheimer disease (AD). The Fyn tyrosine kinase is implicated in AD pathology triggered by amyloid‐ß oligomers (Aßo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD. Methods: The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aßo signaling to Fyn, Pyk2, and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild‐type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, amyloid precursor protein (APP) metabolism, synaptic markers (SV2 and PSD‐95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting. Results: AZD0530 potently inhibits Fyn and prevents both Aßo‐induced Fyn signaling and downstream phosphorylation of the AD risk gene product Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aß metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. Interpretation: Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD. Ann Neurol 2015;77:953–971
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“This reciprocal regulation is further supported by the observation that Aβ-induced Fyn signalling is associated with downstream Pyk2 phosphorylation [68].”
From The new genetic landscape of Alzheimer’s disease: from amyloid cascade to genetically driven synaptic failure hypothesis? (2019) · cites this paper as [68]
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“the most common method to quantify synaptic density has been the quantification of pre-(e.g., synaptophysin [9], synapsin [8]) and post-synaptic (e.g., PSD-95 [10]) genes/proteins”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [10]
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“work from our group and others has shown that quantification of SV2A is similar to that of other markers of synaptic density in clinical samples and after drug challenge”
From Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression (2025) · cites this paper as [10]
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Metadata
- Authors
- Kaufman, A. C., Salazar, S. V., Haas, L. T., Yang, J., Kostylev, M. A., Jeng, A. T., Robinson, S. A., Gunther, E. C., van Dyck, C. H., Nygaard, H. B., & Strittmatter, S. M.
- Affiliations
- Yale University (US)
- Department of Psychiatry Yale University School of Medicine New Haven CT
- Corresponding author
- Strittmatter, Stephen M.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2015-03-21
- Volume
- 77
- Issue
- 6
- Pages
- 953-971
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC4447598
- OpenAlex
- W1725757145
- Cited by
- 314
- References
- 62
- Citations by year
- 2026: 16 · 2025: 13 · 2024: 19 · 2023: 25 · 2022: 28 · 2021: 38 · 2020: 41 · 2019: 28 · 2018: 40 · 2017: 29 · 2016: 24 · 2015: 13
- FWCI
- 25.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UH3-TR000967, R01AG034924)
- BrightFocus Foundation
- Alzheimer's Association
- Falk Medical Research Trust
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, Fyn tyrosine kinase, AZD0530, Src family kinase inhibitor, amyloid-beta oligomers, Pyk2, NMDA receptor NR2B, APP/PS1 mice, spatial memory impairment, synaptic loss, PSD-95, microglial activation, tau phosphorylation, drug repurposing, disease-modifying therapy
- MeSH terms
- Alzheimer Disease, Animals, Behavior, Animal, Disease Models, Animal, Mice, Inbred C57BL, Mice, Transgenic, Quinazolines, Signal Transduction, Amyloid beta-Peptides, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-fyn, Mice, Focal Adhesion Kinase 2, Benzodioxoles
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