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Exp Neurol. 2018 Sep;307:62-73. doi: 10.1016/j.expneurol.2018.05.020. Epub 2018 May 24.

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

Author information

1
Inserm UMR-S 839, Paris, France; Sorbonne Université, Science and Engineering Faculty, Paris, France; Institut du Fer a Moulin, Paris, France; Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigacion Biomedica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain. Electronic address: albertgiralt@ub.edu.
2
Inserm UMR-S 839, Paris, France; Sorbonne Université, Science and Engineering Faculty, Paris, France; Institut du Fer a Moulin, Paris, France. Electronic address: benoit.de-pins@inserm.fr.
3
Inserm UMR-S 839, Paris, France; Sorbonne Université, Science and Engineering Faculty, Paris, France; Institut du Fer a Moulin, Paris, France. Electronic address: carmen.diaz@inserm.fr.
4
Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigacion Biomedica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain. Electronic address: laura.lopezmo12@ub.edu.
5
Inserm UMR-S 839, Paris, France; Sorbonne Université, Science and Engineering Faculty, Paris, France; Institut du Fer a Moulin, Paris, France.
6
Inserm UMR-S 942, Paris, France; Research Memory Center, Paris-Nord Ile-de-France, Saint-Louis-Lariboisière-Fernand Widal Hospital, Paris, France.
7
Univ Lille, CHU Lille, INSERM U1172 "Alzheimer et Tauopathies", LabEx DISTALZ, 59000 Lille, France. Electronic address: vincent.deramecourt@chru-lille.fr.
8
King Abdullah University of Science and Technology (KAUST), Center for Computational Bioscience Research (CBRC), Division of Biological and Environmental Sciences and Engineering (BESE), Thuwal 23955-6900, Saudi Arabia. Electronic address: stefan.arold@kaust.edu.sa.
9
Departament de Biomedicina, Facultat de Medicina, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigacion Biomedica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain. Electronic address: silviagines@ub.edu.
10
Inserm UMR-S 942, Paris, France; Research Memory Center, Paris-Nord Ile-de-France, Saint-Louis-Lariboisière-Fernand Widal Hospital, Paris, France. Electronic address: jacques.hugon@inserm.fr.
11
Inserm UMR-S 839, Paris, France; Sorbonne Université, Science and Engineering Faculty, Paris, France; Institut du Fer a Moulin, Paris, France. Electronic address: jean-antoine.girault@inserm.fr.

Abstract

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.

KEYWORDS:

Alzheimer's disease; Mouse model; Non-receptor tyrosine protein kinase; Pyk2; Src

PMID:
29803828
DOI:
10.1016/j.expneurol.2018.05.020
[Indexed for MEDLINE]

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