Elevated MARK2-Dependent Phosphorylation of Tau in Alzheimer's Disease

Article type: Research Article

Authors: Gu, Gucci Jijuan^a | Wu, Di^a | Lund, Harald^{b; 1} | Sunnemark, Dan^b | Kvist, Alexander J.^c | Milner, Roy^c | Eckersley, Sonia^c | Nilsson, Lars N.G.^{d; 2} | Agerman, Karin^b | Landegren, Ulf^a | Kamali-Moghaddam, Masood^{a; *}

Affiliations: [a] Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden | [b] Department of Neuroscience, iMed, CNS and Pain Södertälje, AstraZeneca Research and Development, Södertälje, Sweden | [c] Antibody Generation Group, Discovery Sciences, iMed, AstraZeneca Research and Development, Mereside, Alderley Park, Macclesfield, Cheshire, UK | [d] Department of Public Health and Caring Sciences, Molecular Geriatrics, Uppsala University, Uppsala, Sweden

Correspondence: [*] Correspondence to: Masood Kamali-Moghaddam, Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, SE-751 85 Uppsala, Sweden. Tel.: +46 18 471 4454; Fax: +46 18 471 4808; E-mail: Masood.Kamali@igp.uu.se.

Note: [1] Present address: Department of Clinical Neuroscience, Centre for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Note: [2] Present address: Department of Pharmacology, Oslo University, Oslo, Norway.

Abstract: The appearance of neurofibrillary tangles (NFT), one of the major hallmarks of Alzheimer's disease (AD), is most likely caused by inappropriate phosphorylation and/or dephosphorylation of tau, eventually leading to the accumulation of NFTs. Enhanced phosphorylation of tau on Ser262 is detected early in the course of the disease and may have a role in the formation of tangles. Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser262 in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser262 in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser262. Furthermore, we observed elevated interactions between MARK2 and tau in post-mortem human AD brains, compared to samples from non-demented elderly controls. Our results from transfected cells demonstrate a specific interaction between MARK2 and tau, as well as MARK2-dependent phosphorylation of tau at Ser262. Furthermore, the elevated interactions between MARK2 and tau in AD brain sections suggests that MARK2 may play an important role in early phosphorylation of tau in AD, possibly qualifying as a therapeutic target for intervention to prevent disease progression.

Keywords: Alzheimer's disease, MARK, phosphorylation, proximity ligation assay, tau

DOI: 10.3233/JAD-2012-121357

Journal: Journal of Alzheimer's Disease, vol. 33, no. 3, pp. 699-713, 2013