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

Huey Jiun Ko, Shean Jaw Chiou, Yu Hui Wong, Yin Hsuan Wang, Yun Ling Lai, Chia Hua Chou, Chihuei Wang, Joon Khim Loh, Ann Shung Lieu, Jiin Tsuey Cheng, Yu Te Lin, Pei Jung Lu, Ming Ji Fann, Chi Ying Huang, Yi Ren Hong*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish
Article number1751
JournalJournal of Clinical Medicine
Volume8
Issue number10
DOIs
StatePublished - Oct 2019

Keywords

  • Alzheimer’s disease
  • Cerebrospinal fluid
  • IPS cells
  • PKA/GSKIP/GSK3β/Tau axis
  • SH-SY5Y

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