PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

Abstract

Background Cognitive impairment in humans with Alzheimer's disease (AD) and in animal models of Aβ-pathology can be ameliorated by treatments with the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ) agonists, such as rosiglitazone (RSG). Previously, we demonstrated that in the Tg2576 animal model of AD, RSG treatment rescued cognitive deficits and reduced aberrant activity of granule neurons in the dentate gyrus (DG), an area critical for memory formation. Methods We used a combination of mass spectrometry, confocal imaging, electrophysiology and split-luciferase assay and in vitro phosphorylation and Ingenuity Pathway Analysis. Results Using an unbiased, quantitative nano-LC-MS/MS screening, we searched for potential molecular targets of the RSG-dependent rescue of DG granule neurons. We found that S226 phosphorylation of fibroblast growth factor 14 (FGF14), an accessory protein of the voltage-gated Na+ (Nav) channels required for neuronal firing, was reduced in Tg2576 mice upon treatment with RSG. Using confocal microscopy, we confirmed that the Tg2576 condition decreased PanNav channels at the AIS of the DG, and that RSG treatment of Tg2576 mice reversed the reduction in PanNav channels. Analysis from previously published data sets identified correlative changes in action potential kinetics in RSG-treated T2576 compared to untreated and wildtype controls. In vitro phosphorylation and mass spectrometry confirmed that the multifunctional kinase GSK–3β, a downstream target of insulin signaling highly implicated in AD, phosphorylated FGF14 at S226. Assembly of the FGF14:Nav1.6 channel complex and functional regulation of Nav1.6-mediated currents by FGF14 was impaired by a phosphosilent S226A mutation. Bioinformatics pathway analysis of mass spectrometry and biochemistry data revealed a highly interconnected network encompassing PPARγ, FGF14, SCN8A (Nav 1.6), and the kinases GSK–3 β, casein kinase 2β, and ERK1/2. Conclusions These results identify FGF14 as a potential PPARγ-sensitive target controlling Aβ-induced dysfunctions of neuronal activity in the DG underlying memory loss in early AD.

Imputation-Based Whole-Genome Sequence Association Study Reveals Constant and Novel Loci for Hematological Traits in a Large-Scale Swine F2 Resource Population

“…FGF14 was identified to be associated with neuronal signaling in mice ( Wang et al, 2002 ). Recent studies on the FGF14 gene focused on neurology in humans and in mice ( Amado et al, 2017 ; Di Re et al, 2017 ; Hsu et al, 2017 ). Interestingly, this gene was also identified to be a candidate for teat number in Duroc pigs ( Tan et al, 2017 ), implying the pleiotropy of FGF14 .…”

Systems pharmacology-based approach to investigate the mechanisms of Danggui-Shaoyao-san prescription for treatment of Alzheimer’s disease

“…Figure 5 b showcases the top 10 significant KEGG pathways ( q < 0.05), and some of them are intensively correlated with AD treatment. For instance, PPAR signaling pathway (ko03320) has been demonstrated to increase phosphorylation of fibroblast growth factor 14 in the Tg2576 mouse model of AD [ 53 ]. Furthermore, a recent study shows that bile secretion (ko04976) is associated with “A/T/N”(amyloid, tau, and neurodegeneration) AD biomarkers, providing further support for a role of bile acid pathway in AD pathophysiology [ 54 ].…”

Long noncoding RNA FGF14-AS2 inhibits breast cancer metastasis by regulating the miR-370-3p/FGF14 axis

“…FGF14, as a member of the nonsecreted intracellular FGF family, does not function as an FGF ligand 29 . Previous studies on FGF14 mainly focused on its functions in neural cells 30,31 . Interestingly, a recent study revealed that FGF14 is repressed in patients with nasopharyngeal carcinoma, and FGF14 overexpression suppresses cell proliferation 32 .…”