PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer's disease - Institut du Fer à Moulin Access content directly
Journal Articles Experimental Neurology Year : 2018

PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer's disease

Benoit de Pins
  • Function : Author
Carmen Cifuentes-Díaz
  • Function : Author
Laura López-Molina
  • Function : Author
Amel Thamila Farah
  • Function : Author
Marion Tible
  • Function : Author
Vincent Deramecourt
  • Function : Author
  • PersonId : 1226152
Stefan T Arold
  • Function : Author
  • PersonId : 1113650
Silvia Ginés
  • Function : Author
  • PersonId : 1222292
Jacques Hugon
  • Function : Author
  • PersonId : 928917

Abstract

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 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.

Keywords

long term potentiation mGluR5 metabotropic glutamate receptor 5 NIH National Institute of Health NMDA N-methyl-D-aspartate PLA proximity ligation assay PrPc cellular prion protein PSD-95 95 kDa PTK2B protein tyrosine kinase 2B Pyk2 proline-rich tyrosine kinase 2 SDS sodium dodecyl sulfate SEM standard error of the mean SFK Src-family kinase STEP striatal enriched phosphatase STM short term memory WT Alzheimer's disease Mouse model Non-receptor tyrosine protein kinase Pyk2 Src 5XFAD mice transgenic for human APP and presenilin1 with 5 mutations found in familial Alzheimer's disease AAV adeno-associated virus Aβ amyloid β AD Alzheimer's disease ANOVA analysis of variance APP amyloid precursor protein CA1/3 cornu Ammoni 1/3 DAPI 4′ 6-diamidine-2′-phenylindole DG dentate gyrus FAK focal adhesion kinase GFAP glial fibrillary acidic protein GFP green fluorescent protein IB immunoblotting IF immunofluorescence Inserm LTM long term memory LTP long term potentiation mGluR5 metabotropic glutamate receptor 5 NIH National Institute of Health NMDA N-methyl-D-aspartate PLA proximity ligation assay PrPc cellular prion protein PSD-95 post-synaptic density protein 95 kDa PTK2B protein tyrosine kinase 2B Pyk2 proline-rich tyrosine kinase 2 SDS sodium dodecyl sulfate SEM standard error of the mean SFK Src-family kinase STEP striatal enriched phosphatase STM short term memory WT wild type mice transgenic for human APP and presenilin1 with 5 mutations found in familial Alzheimer's disease AAV adeno-associated virus amyloid β AD Alzheimer's disease ANOVA analysis of variance APP amyloid precursor protein CA1/3 cornu Ammoni 1/3 DAPI 4′ 6-diamidine-2′-phenylindole DG dentate gyrus FAK focal adhesion kinase GFAP glial fibrillary acidic protein GFP green fluorescent protein IB immunoblotting IF immunofluorescence Inserm long term memory LTP Alzheimer's disease mouse model non-receptor tyrosine protein kinase Pyk2 Src mouse model non-receptor tyrosine protein kinase Src
Fichier principal
Vignette du fichier
Giralt-et-al_Final-accepted-version.pdf (601.35 Ko) Télécharger le fichier
Origin Files produced by the author(s)

Dates and versions

hal-03983787 , version 1 (27-02-2023)

Identifiers

Cite

Albert Giralt, Benoit de Pins, Carmen Cifuentes-Díaz, Laura López-Molina, Amel Thamila Farah, et al.. PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer's disease. Experimental Neurology, 2018, 307, pp.62-73. ⟨10.1016/j.expneurol.2018.05.020⟩. ⟨hal-03983787⟩
10 View
58 Download

Altmetric

Share

Gmail Mastodon Facebook X LinkedIn More