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

Abstract

Pyk2 is a Ca-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.

FAK family kinases in brain health and disease

“…Activation of FAK was also observed in the olfactory bulb of AD patients, where dysfunction is considered as an early event in disease prognosis [31]. These data suggest that FAK may have a compensatory role for Pyk2 in AD, and that the lack of synaptic and behavioral phenotype in AD mice in which Pyk2 was genetically deleted [23] may be explained, at least in part, by a compensatory effect of FAK [32].…”

“…Although it has long been assumed that a deletion of Pyk2 should improve the prognosis or the symptoms of AD, no change in synaptic functions or in hippocampus-dependent learning and memory was observed in an AD mouse model in which Pyk2 was genetically depleted. Nevertheless, overexpression of Pyk2 in the hippocampus of AD mice significantly improved their memory and learning ability due to increase in Pyk2 activation levels and a consequent decrease in Src cleavage which results in the formation of a neurotoxic form of Src kinase [23].…”

Genetic Association of FERMT2, HLA-DRB1, CD2AP, and PTK2B Polymorphisms With Alzheimer’s Disease Risk in the Southern Chinese Population

“…The interaction between PTK2B and hyperphosphorylated and oligomeric Tau in the brain is involved in pathophysiological processes of AD (Dourlen et al, 2017). In a mouse model of AD, the levels of PTK2B Tyr-402 phosphorylation were shown to be reduced in the hippocampus, and the behavioral and molecular phenotype could be rescued by PTK2B overexpression (Giralt et al, 2018). Although the rs28834970 of PTK2B has been identified to be a genetic contributor to the susceptibility of LOAD in several studies (Lambert et al, 2013;Jiao et al, 2015), no studies, to date, have investigated whether this genetic polymorphism is associated with EOAD.…”

Conditional BDNF delivery from astrocytes rescues memory deficits, spine density and synaptic properties in the 5xFAD mouse model of Alzheimer disease

“…To explore changes in excitatory synapses likely associated with spine alterations, we evaluated presynaptic and postsynaptic markers. We examined the number of positive clusters for PSD-95 and synaptophysin, which are postsynaptic and presynaptic markers, respectively, previously reported to be decreased in 5xFAD mice, correlating with cognitive decline (Yang et al, 2015;Giralt et al, 2018). We analyzed these two markers in CA1 stratum radiatum of 8-month-old mice.…”