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Open AccessArticle

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

1
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
2
Department of Biochemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
3
Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
4
Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan
5
Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan
6
Department of Neurosurgery, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
7
Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan
8
Section of Neurology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
9
Institute of Clinical Medicine, School of Medicine, National Cheng Kung University, Tainan 701, Taiwan
10
Department of Life Sciences and Institute of Genome Sciences and Brain Research Center, National Yang-Ming University, Taipei 11221, Taiwan
11
Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan; Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally.
J. Clin. Med. 2019, 8(10), 1751; https://doi.org/10.3390/jcm8101751
Received: 1 October 2019 / Revised: 17 October 2019 / Accepted: 17 October 2019 / Published: 21 October 2019
(This article belongs to the Special Issue Energetic Metabolism Impairment in Brain Dysfunction)
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. View Full-Text
Keywords: PKA/GSKIP/GSK3β/Tau axis; SH-SY5Y; iPS cells; cerebrospinal fluid; Alzheimer’s disease PKA/GSKIP/GSK3β/Tau axis; SH-SY5Y; iPS cells; cerebrospinal fluid; Alzheimer’s disease
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MDPI and ACS Style

Ko, H.-J.; Chiou, S.-J.; Wong, Y.-H.; Wang, Y.-H.; Lai, Y.-L.; Chou, C.-H.; Wang, C.; Loh, J.-K.; Lieu, A.-S.; Cheng, J.-T.; Lin, Y.-T.; Lu, P.-J.; Fann, M.-J.; Huang, C.-Y.; Hong, Y.-R. 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, 8, 1751.

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