Harald Lund 1, Richard F Cowburn, Elin Gustafsson, Kia Strömberg, Anne Svensson, Leif Dahllund, David Malinowsky, Dan Sunnemark
Brain Pathol. 2013 Jul;23(4):378-89.
DOI: https://doi.org/10.1111/bpa.12001
Abstract
Recent reports have implicated tau-tubulin kinase 1 (TTBK1) in the pathological phospho-
rylation of tau that occurs in Alzheimer’s disease (AD).
The present study was undertaken to provide an extensive characterization of
TTBK1 mRNA and protein expression in human brain from AD cases and non-demented
controls so as to better understand the disease relevance of this novel kinase. In situ
hybridization and immunohistochemistry revealed abundant expression of TTBK1 in the
somatodedritic compartment of cortical and hippocampal neurons of both AD cases and
controls. TTBK1 immunoreactivity appeared to vary with the level of phospho-tau stain-
ing, and was strong in the somatodendritic compartment of apparently healthy hippocampal
neurons as well as in pre-tangle neurons where it co-localized with diffuse phospho-Ser422
tau staining. Ser422 was confirmed as a TTBK1 substrate in vitro, and an antibody towards
the site, in addition to labeling AT8-positive neurofibrillary tangles (NFTs), neuritic
plaques and neuropil threads, also labeled a small population of neurons that were unla-
beled with AT8.
These data suggest a role for TTBK1 in pre-tangle formation prior to the formation of
fibrillar tau and strengthen the idea that tau is phosphorylated at Ser422 at an early/
intermediate stage in NFT formation.
