2. Academic Validation
  3. GSKIP-Mediated Anchoring Increases Phosphorylation of Tau by PKA but Not by GSK3beta via cAMP/PKA/GSKIP/GSK3/Tau Axis Signaling in Cerebrospinal Fluid and iPS Cells in Alzheimer Disease

GSKIP-Mediated Anchoring Increases Phosphorylation of Tau by PKA but Not by GSK3beta via cAMP/PKA/GSKIP/GSK3/Tau Axis Signaling in Cerebrospinal Fluid and iPS Cells in Alzheimer Disease

  • J Clin Med. 2019 Oct 21;8(10):1751. doi: 10.3390/jcm8101751.
Huey-Jiun Ko 1 2,  Shean-Jaw Chiou 3 4 5,  Yu-Hui Wong 6,  Yin-Hsuan Wang 7 8,  YunLing Lai 9 10,  Chia-Hua Chou 11 12,  Chihuei Wang 13,  Joon-Khim Loh 14 15,  Ann-Shung Lieu 16 17,  Jiin-Tsuey Cheng 18,  Yu-Te Lin 19,  Pei-Jung Lu 20,  Ming-Ji Fann 21,  Chi-Ying F Huang 22 23,  Yi-Ren Hong 24 25 26 27
Affiliations

Affiliations

  • 1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 2 Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 3 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 4 Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 5 Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. [email protected].
  • 6 Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan. [email protected].
  • 7 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 8 Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 9 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 10 Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 11 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 12 Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 13 Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 14 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 15 Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. [email protected].
  • 16 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 17 Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. [email protected].
  • 18 Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan. [email protected].
  • 19 Section of Neurology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan. [email protected].
  • 20 Institute of Clinical Medicine, School of Medicine, National Cheng Kung University, Tainan 701, Taiwan. [email protected].
  • 21 Department of Life Sciences and Institute of Genome Sciences and Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan. [email protected].
  • 22 Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 23 Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan. [email protected].
  • 24 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 25 Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan. [email protected].
  • 26 Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. [email protected].
  • 27 Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan. [email protected].
PMID: 31640277 DOI: 10.3390/jcm8101751
Abstract

Based on the protein kinase A (PKA)/GSK3β interaction protein (GSKIP)/glycogen synthase kinase 3β (GSK3β) axis, we hypothesized that these might play a role in Tau phosphorylation. Here, we report that the phosphorylation of Tau Ser409 in SHSY5Y cells was increased by overexpression of GSKIP WT more than by PKA- and GSK3β-binding defective mutants (V41/L45 and L130, respectively). We conducted in vitro assays of various kinase combinations to show that a combination of GSK3β with PKA but not Ca2+/calmodulin-dependent protein kinase II (CaMK II) might provide a conformational shelter to harbor Tau Ser409. Cerebrospinal fluid (CSF) was evaluated to extend the clinical significance of Tau phosphorylation status in Alzheimer's disease (AD), neurological disorders (NAD), and mild cognitive impairment (MCI). We found higher levels of different PKA-Tau phosphorylation sites (Ser214, Ser262, and Ser409) in AD than in NAD, MCI, and normal groups. Moreover, we used the CRISPR/Cas9 system to produce amyloid precursor protein (APPWT/D678H) isogenic mutants. These results demonstrated an enhanced level of phosphorylation by PKA but not by the control. This study is the first to demonstrate a transient increase in phosphor-Tau caused by PKA, but not GSK3β, in the CSF and induced pluripotent stem cells (iPSCs) of AD, implying that both GSKIP and GSK3β function as anchoring proteins to strengthen the cAMP/PKA/Tau axis signaling during AD pathogenesis.

Keywords

Alzheimer’s disease; PKA/GSKIP/GSK3β/Tau axis; SH-SY5Y; cerebrospinal fluid; iPS cells.

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