PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer's disease
de Pins, Benoît
Farah, Amel Thamila
Arold, Stefan T.
KAUST DepartmentBiological and Environmental Sciences and Engineering (BESE) Division
Computational Bioscience Research Center (CBRC)
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
KAUST Grant NumberOSR-2015-CRG4-2602
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AbstractPyk2 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 at 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 effect 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.
CitationGiralt A, de Pins B, Cifuentes-Díaz C, López-Molina L, Farah AT, et al. (2018) PTK2B/Pyk2 overexpression improves a mouse model of Alzheimer’s disease. Experimental Neurology. Available: http://dx.doi.org/10.1016/j.expneurol.2018.05.020.
SponsorsThis work was supported in part by Inserm, Sorbonne-Université (formerly Université Pierre et Marie Curie, UPMC, Paris-6), and grants from ANR MALZ-2013 to JH and JAG, the King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research award (#OSR-2015-CRG4-2602) to SA and JAG, and Ministerio de Ciencia e Innovación (SAF2015- 67474-R;MINECO/FEDER to SG. Equipment at the IFM was also supported by DIM NeRF from Région Ile-de-France and by the FRC/Rotary “Espoir en tête”. AG is a Ramón y Cajal fellow (RYC-2016-19466). The Girault’s lab is affiliated with the Paris School of Neuroscience (ENP) and the “Biology for Psychiatry” laboratory of excellence “Bio-Psy labex”. Imaging was carried out at the Institut du Fer à Moulin “Cell and Tissue Imaging facility”. We are grateful to the Banc de Teixits Neurològics (Biobanc-HC-IDIBAPS) for providing brain samples from control subjects and AD patients.
Except where otherwise noted, this item's license is described as NOTICE: this is the author’s version of a work that was accepted for publication in Experimental Neurology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Experimental Neurology, [, , (2018-05-24)] DOI: 10.1016/j.expneurol.2018.05.020 . © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/