Title

Role of individual MARK isoforms in phosphorylation of tau at Ser²⁶² in Alzheimer's disease.

Journal

Neuromolecular medicine

Volume

15

Issue

None

Pages

458-69

Date

2013-09-01

Authors

Blokzijl A | Classon C | Gu GJ | Kamali-Moghaddam M | Landegren U | Lund H | Sunnemark D | Wu D | von Euler G

In 293T culture, MB decreased MARK4-mediated Tau phosphorylation in a dose dependent manner. MB down-regulates MARK4 protein level through ubiquitin-proteasome pathway and inhibition of MARK4 kinase activity in vitro.

In parallel, phosphorylation of tau at Ser262 in MARK-transfected cells was investigated using a rabbit antibody recognizing phosphorylated Ser262 of tau (AGG5759) and a mouse anti-tau antibody (SC-21796) (Fig. S1a3). Tau was shown to interact with each of the transfected MARK isoforms (Fig. 1) and to be phosphorylated at Ser262 (Fig. 2). Staurosporine, a non-selective kinase inhibitor, significantly inhibited interactions between tau and each of the four MARK isoforms after treatment with 20 lM staurosporine for 1 h (Fig. 1; p = 0.02 for MARK1–, MARK2– and MARK3–tau interactions and p = 3 9 10-6 for MARK4–tau interaction). Treatment with staurosporine also significantly reduced PLA signals for tau phosphorylation at Ser262 (Fig. 2; p = 0.04 for MARK1- and p = 0.02 for MARK2- and MARK3- and p = 1 9 10-5 for MARK4-mediated tau phosphorylation)

In cells, a CagA peptide inhibited tau phosphorylation at Ser²6² mediated by MARK4 but not other MARK isoforms. A strong and significant elevation of MARK4 expression and MARK4-tau interactions in AD brains correlated with the Braak stages of the disease.

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