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

Wei Chun J. Hsu, Norelle C. Wildburger, Sigmund J. Haidacher, Miroslav N. Nenov, Oluwarotimi Folorunso, Aditya K. Singh, Brent C. Chesson, Whitney F. Franklin, Ibdanelo Cortez, Rovshan Sadygov, Kelly Dineley, Jay S. Rudra, Giulio Taglialatela, Cheryl F. Lichti, Larry Denner, Fernanda Laezza

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1-17
Number of pages17
JournalExperimental Neurology
Volume295
DOIs
StatePublished - Sep 1 2017

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rosiglitazone
PPAR gamma
Alzheimer Disease
Dentate Gyrus
Phosphorylation
Mass Spectrometry
Phosphotransferases
Animal Models
Neurons
Casein Kinase II
Electrophysiology
Memory Disorders
Cytoplasmic and Nuclear Receptors
Computational Biology
Luciferases
Confocal Microscopy
Biochemistry
Action Potentials
fibroblast growth factor 14
Insulin

Keywords

  • Alzheimer's disease
  • Confocal microscopy
  • Fibroblast growth factor 14
  • Mass spectrometry
  • PPARgamma

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease. / Hsu, Wei Chun J.; Wildburger, Norelle C.; Haidacher, Sigmund J.; Nenov, Miroslav N.; Folorunso, Oluwarotimi; Singh, Aditya K.; Chesson, Brent C.; Franklin, Whitney F.; Cortez, Ibdanelo; Sadygov, Rovshan; Dineley, Kelly; Rudra, Jay S.; Taglialatela, Giulio; Lichti, Cheryl F.; Denner, Larry; Laezza, Fernanda.

In: Experimental Neurology, Vol. 295, 01.09.2017, p. 1-17.

Research output: Contribution to journalArticle

Hsu, WCJ, Wildburger, NC, Haidacher, SJ, Nenov, MN, Folorunso, O, Singh, AK, Chesson, BC, Franklin, WF, Cortez, I, Sadygov, R, Dineley, K, Rudra, JS, Taglialatela, G, Lichti, CF, Denner, L & Laezza, F 2017, 'PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease', Experimental Neurology, vol. 295, pp. 1-17. https://doi.org/10.1016/j.expneurol.2017.05.005
Hsu, Wei Chun J. ; Wildburger, Norelle C. ; Haidacher, Sigmund J. ; Nenov, Miroslav N. ; Folorunso, Oluwarotimi ; Singh, Aditya K. ; Chesson, Brent C. ; Franklin, Whitney F. ; Cortez, Ibdanelo ; Sadygov, Rovshan ; Dineley, Kelly ; Rudra, Jay S. ; Taglialatela, Giulio ; Lichti, Cheryl F. ; Denner, Larry ; Laezza, Fernanda. / PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease. In: Experimental Neurology. 2017 ; Vol. 295. pp. 1-17.
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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.",
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T1 - PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer's disease

AU - Hsu, Wei Chun J.

AU - Wildburger, Norelle C.

AU - Haidacher, Sigmund J.

AU - Nenov, Miroslav N.

AU - Folorunso, Oluwarotimi

AU - Singh, Aditya K.

AU - Chesson, Brent C.

AU - Franklin, Whitney F.

AU - Cortez, Ibdanelo

AU - Sadygov, Rovshan

AU - Dineley, Kelly

AU - Rudra, Jay S.

AU - Taglialatela, Giulio

AU - Lichti, Cheryl F.

AU - Denner, Larry

AU - Laezza, Fernanda

PY - 2017/9/1

Y1 - 2017/9/1

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Confocal microscopy

KW - Fibroblast growth factor 14

KW - Mass spectrometry

KW - PPARgamma

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