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PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer's disease
Copyright policy ) Giralt, Albert; de Pins, Benoit; Cifuentes-Díaz, Carmen; López-Molina, Laura; Farah, Amel Thamila; Tible, Marion; Deramecourt, Vincent; +4 Authors
Giralt, Albert; de Pins, Benoit; Cifuentes-Díaz, Carmen; López-Molina, Laura; Farah, Amel Thamila; Tible, Marion; Deramecourt, Vincent; Arold, Stefan; Ginés, Silvia; Hugon, Jacques; Girault, Jean-Antoine;
PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer's disease
Pyk2 is a Ca2+-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 and increased following overexpression. Our results show that Pyk2 is not essential for the pathogenic effects of human amyloidogenic mutations in the 5XFAD mouse model. However, the slight decrease in plaque number observed in these mice in the absence of Pyk2 and their increase following Pyk2 overexpression suggest a contribution of this kinase in plaque formation. Importantly, a decreased function of Pyk2 was observed in 5XFAD mice, indicated by its decreased autophosphorylation and associated Src alterations. Overcoming this deficit by Pyk2 overexpression improved the behavioral and molecular phenotype of 5XFAD mice. Thus, our results in a mouse model of AD suggest that Pyk2 impairment may play a role in the symptoms of the disease.
- Sorbonne Paris Cité France
- University of Lille France
- Paris 13 University France
- Inserm France
- University of Paris France
green fluorescent protein, Male, Non-receptor tyrosine protein kinase, immunofluorescence Inserm, Plaque, Amyloid, non-receptor tyrosine protein kinase, Mice, amyloid precursor protein CA1/3, DAPI 4′, N-methyl-D-aspartate PLA, Alzheimer's disease ANOVA, proline-rich tyrosine kinase 2, mGluR5, proline-rich tyrosine kinase 2 SDS, Aged, 80 and over, Cerebral Cortex, ANOVA, WT, short term memory WT, GFAP, metabotropic glutamate receptor 5, adeno-associated virus Aβ, proximity ligation assay PrPc, metabotropic glutamate receptor 5 NIH, 6-diamidine-2′-phenylindole, 6-diamidine-2′-phenylindole DG, [SDV] Life Sciences [q-bio], 95 kDa PTK2B, Alzheimer's disease mouse model non-receptor tyrosine protein kinase Pyk2 Src, Inserm, PLA, LTM, amyloid β, LTP, long term memory LTP, immunoblotting, Locomotion, Src, 570, standard error of the mean SFK, mouse model, 610, cornu Ammoni 1/3 DAPI 4′, adeno-associated virus, Gene Expression Regulation, Enzymologic, Protein metabolism, PTK2B, Alzheimer Disease, Humans, 95 kDa, proximity ligation assay, Maze Learning, NIH, FAK, IF, mice transgenic for human APP and presenilin1 with 5 mutations found in familial Alzheimer's disease AAV, focal adhesion kinase, IB, AD, focal adhesion kinase GFAP, Malaltia d'Alzheimer, Focal Adhesion Kinase 2, NMDA, protein tyrosine kinase 2B Pyk2, Metabolisme de proteïnes, APP, National Institute of Health NMDA, cellular prion protein PSD-95, green fluorescent protein IB, mice transgenic for human APP and presenilin1 with 5 mutations found in familial Alzheimer's disease, long term potentiation mGluR5, PrPc, STM, analysis of variance APP, DG, amyloid precursor protein, Hippocampus, striatal enriched phosphatase STM, dentate gyrus, long term potentiation, SDS, Src-family kinase STEP, Aβ, post-synaptic density protein, Alzheimer's disease Mouse model Non-receptor tyrosine protein kinase Pyk2 Src 5XFAD, AAV, Alzheimer's disease, STEP, sodium dodecyl sulfate SEM, cellular prion protein, sodium dodecyl sulfate, glial fibrillary acidic protein, SEM, standard error of the mean, Female, wild type, analysis of variance, Mice, Transgenic, SFK, GFP, Mouse model, short term memory, amyloid β AD, cornu Ammoni 1/3, Animals, Src-family kinase, immunofluorescence, PSD-95, long term memory, Pyk2, dentate gyrus FAK, immunoblotting IF, Disease Models, Animal, CA1/3, N-methyl-D-aspartate, glial fibrillary acidic protein GFP, National Institute of Health, protein tyrosine kinase 2B, striatal enriched phosphatase
green fluorescent protein, Male, Non-receptor tyrosine protein kinase, immunofluorescence Inserm, Plaque, Amyloid, non-receptor tyrosine protein kinase, Mice, amyloid precursor protein CA1/3, DAPI 4′, N-methyl-D-aspartate PLA, Alzheimer's disease ANOVA, proline-rich tyrosine kinase 2, mGluR5, proline-rich tyrosine kinase 2 SDS, Aged, 80 and over, Cerebral Cortex, ANOVA, WT, short term memory WT, GFAP, metabotropic glutamate receptor 5, adeno-associated virus Aβ, proximity ligation assay PrPc, metabotropic glutamate receptor 5 NIH, 6-diamidine-2′-phenylindole, 6-diamidine-2′-phenylindole DG, [SDV] Life Sciences [q-bio], 95 kDa PTK2B, Alzheimer's disease mouse model non-receptor tyrosine protein kinase Pyk2 Src, Inserm, PLA, LTM, amyloid β, LTP, long term memory LTP, immunoblotting, Locomotion, Src, 570, standard error of the mean SFK, mouse model, 610, cornu Ammoni 1/3 DAPI 4′, adeno-associated virus, Gene Expression Regulation, Enzymologic, Protein metabolism, PTK2B, Alzheimer Disease, Humans, 95 kDa, proximity ligation assay, Maze Learning, NIH, FAK, IF, mice transgenic for human APP and presenilin1 with 5 mutations found in familial Alzheimer's disease AAV, focal adhesion kinase, IB, AD, focal adhesion kinase GFAP, Malaltia d'Alzheimer, Focal Adhesion Kinase 2, NMDA, protein tyrosine kinase 2B Pyk2, Metabolisme de proteïnes, APP, National Institute of Health NMDA, cellular prion protein PSD-95, green fluorescent protein IB, mice transgenic for human APP and presenilin1 with 5 mutations found in familial Alzheimer's disease, long term potentiation mGluR5, PrPc, STM, analysis of variance APP, DG, amyloid precursor protein, Hippocampus, striatal enriched phosphatase STM, dentate gyrus, long term potentiation, SDS, Src-family kinase STEP, Aβ, post-synaptic density protein, Alzheimer's disease Mouse model Non-receptor tyrosine protein kinase Pyk2 Src 5XFAD, AAV, Alzheimer's disease, STEP, sodium dodecyl sulfate SEM, cellular prion protein, sodium dodecyl sulfate, glial fibrillary acidic protein, SEM, standard error of the mean, Female, wild type, analysis of variance, Mice, Transgenic, SFK, GFP, Mouse model, short term memory, amyloid β AD, cornu Ammoni 1/3, Animals, Src-family kinase, immunofluorescence, PSD-95, long term memory, Pyk2, dentate gyrus FAK, immunoblotting IF, Disease Models, Animal, CA1/3, N-methyl-D-aspartate, glial fibrillary acidic protein GFP, National Institute of Health, protein tyrosine kinase 2B, striatal enriched phosphatase
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).49 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10% views 118 downloads 103 - 118views103downloads
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This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
Citations provided by BIP!popularityPopularity provided by BIP!
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
Popularity provided by BIP!influenceInfluence provided by BIP!
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
Influence provided by BIP!impulseImpulse provided by BIP!
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
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