PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer's disease
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Pyk2 is a Ca 2+ -activated non-receptor tyrosine kinase enriched in forebrain neurons and involved in synaptic regulation. Human genetic studies associated PTK2B, the gene coding Pyk2, with risk for Alzheimer's disease (AD). We previously showed that Pyk2 is important for hippocampal function, plasticity, and spine structure. However, its potential role in AD is unknown. To address this question we used human brain samples and 5XFAD mice, an amyloid mouse model of AD expressing mutated human amyloid precursor protein and presenilin1. In the hippocampus of 5XFAD mice and in human AD patients' cortex and hippocampus, Pyk2 total levels were normal. However, Pyk2 Tyr-402 phosphorylation levels, reflecting its autophosphorylation-dependent activity, were reduced in 5XFAD mice at 8 months of age but not 3 months. We crossed these mice with Pyk2 -/- mice to generate 5XFAD animals devoid of Pyk2. At 8 months the phenotype of 5XFAD x Pyk2 -/- double mutant mice was not different from that of 5XFAD. In contrast, overexpression of Pyk2 in the hippocampus of 5XFAD mice, using adeno-associated virus, rescued autophosphorylated Pyk2 levels and improved synaptic markers and performance in several behavioral tasks. Both Pyk2 -/- and 5XFAD mice showed an increase of potentially neurotoxic Src cleavage product, which was rescued by Pyk2 overexpression. Manipulating Pyk2 levels had only minor effects on Aβ plaques, which were slightly decreased in hippocampus CA3 region of double mutant mice an…
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Synaptic fragility/sensitivity was proposed as a pathological trigger depending on genetic risk factors, some of which have already been linked to synaptic mechanisms such as BIN1, FERMT2, PTK2B or CD2AP.
“we proposed synaptic fragility/sensitivity as a pathological trigger10, depending on genetic risk factors, some of which have already been linked to synaptic mechanisms, such as BIN1, FERMT2, PTK2B or CD2AP9–12.”
From PLCG2 downregulation impairs synaptic function and increases Alzheimer’s disease hallmarks in neuronal cultures (2026) · cites this paper as [11]
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- Authors
- Giralt, A., de Pins, B., Cifuentes-Díaz, C., López-Molina, L., Farah, A. T., Tible, M., Deramecourt, V., Arold, S. T., Ginés, S., Hugon, J., & Girault, J.-A.
- Affiliations
- Inserm (FR)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- King Abdullah University of Science and Technology (SA)
- Corresponding author
- Girault, Jean-Antoine
- ORCID
- Venue
- Experimental Neurology
- Publisher
- Elsevier BV
- Published
- 2018-09
- Volume
- 307
- Pages
- 62-73
- ISSN
- 0014-4886 (ISSN-L)
- OpenAlex
- W2803712955
- Cited by
- 64
- References
- 62
- Citations by year
- 2026: 12 · 2025: 6 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 9 · 2018: 3
- FWCI
- 4.47
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- cc-by-nc-nd
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- Locations
- Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (acceptedVersion, cc-by-nc-nd)
- HAL (submittedVersion, other-oa)
- King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Inserm
- Sorbonne-Université (ANR MALZ-2013)
- King Abdullah University of Science and Technology ((#OSR-2015-CRG4-2602)
- Ministerio de Ciencia e Innovación (SAF2015-67474-R))
- MINECO
- FEDER
- Ramón y Cajal (RYC-2016-19466)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Pyk2, Alzheimer's disease, 5xFAD mice, amyloid plaques, Src family kinases, non-receptor tyrosine kinase, hippocampus, synaptic function, adeno-associated virus overexpression, autophosphorylation, amyloid precursor protein, presenilin 1, neuroprotection
- MeSH terms
- Aged, 80 and over, Alzheimer Disease, Animals, Cerebral Cortex, Disease Models, Animal, Female, Hippocampus, Humans, Locomotion, Male, Mice, Transgenic, Gene Expression Regulation, Enzymologic, Maze Learning, Mice, Focal Adhesion Kinase 2, Plaque, Amyloid
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