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.

Ko Ko,Wong Wong,Lu Lu,Chiou Chiou,Lai Lai,Cheng Cheng,Hong Hong,Wang Wang,Lieu Lieu,Lin Lin,Chou Chou,Fann Fann,Huang Huang,Loh Loh

doi:10.3390/jcm8101751

Ko Ko, Wong Wong + Show 12 more

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https://doi.org/10.3390/jcm8101751

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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.

Highlights

glycogen synthase kinase 3β (GSK3β) interaction protein (GSKIP) is the smallest A-kinase anchor protein (AKAP) [1,2]
We recently identified residue L130 of GSK3β interaction protein (GSKIP) as a critical point for binding with GSK3β, and the L130P GSKIP mutant resulted in loss of inhibition of neurite outgrowth in human neuroblastoma SH-SY5Y cells [5]
Further studies have demonstrated that mammalian GSKIP favors dimer instead of monomer because the V41/L45 sites are distal to the L130 residue in the GSKIP monomer formation, preventing mutual interactions between protein kinase A (PKA) RII and the GSK3β binding region, indicating that L130 point mutation is essential for the GSK3β binding function [7,9]

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Introduction

GSK3β interaction protein (GSKIP) is the smallest A-kinase anchor protein (AKAP) [1,2]. The loss of the peroxisome proliferator-activated receptor gamma-E2F1 (PPARγ-E2F1) axis in the lungs was found to lead to a deficient complex with Wnt signaling that caused downregulation of GSKIP and eventually resulted in decreased angiogenesis, indicating that GSKIP may be involved in PPARγ-related angiogenic potential in mature pulmonary microvascular endothelial cells (PMVECs) through E2F1 [13]. These findings prompt us to believe that GSKIP has a role in neurodevelopment. Clarifying the roles of these would help advance drug development for neuron-related disorders such as Alzheimer’s disease (AD)

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