Role of Individual MARK Isoforms in Phosphorylation of Tau at Ser262 in Alzheimer’s Disease
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The microtubule-affinity regulating kinase (MARK) family consists of four highly conserved members that have been implicated in phosphorylation of tau protein, causing formation of neurofibrillary tangles in Alzheimer’s disease (AD). Understanding of roles by individual MARK isoform in phosphorylating tau has been limited due to lack of antibodies selective for each MARK isoform. In this study, we first applied the proximity ligation assay on cells to select antibodies specific for each MARK isoform. In cells, a CagA peptide specifically and significantly inhibited tau phosphorylation at Ser262 mediated by MARK4 but not other MARK isoforms. We then used these antibodies to study expression levels of MARK isoforms and interactions between tau and individual MARK isoforms in postmortem human brains. We found a strong and significant elevation of MARK4 expression and MARK4–tau interactions in AD brains, correlating with the Braak stages of the disease. These results suggest the MARK4–tau interactions are of functional importance in the progression of AD and the results also identify MARK4 as a promising target for AD therapy.
KeywordsAlzheimer’s disease MARK Phosphorylation Proximity ligation Tau
This work was funded by Uppsala Berzelii Technology Centre for Neurodiagnostics, the Knut and Alice Wallenberg Foundation, the Swedish Research Council for medicine (2007–2720, UL) and by the European Community’s 6th and 7th Framework Programs. We thank the Netherland Brain Bank for postmortem human brains.
Conflict of interest
U.L. is a cofounder of Olink Bioscience that commercializes the in situ PLA technology.
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