title: Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho-Ser422 tau in the Alzheimer's disease brain.
abstract: Recent reports have implicated tau-tubulin kinase 1 (TTBK1) in the pathological phosphorylation 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 somatodendritic compartment of cortical and hippocampal neurons of both AD cases and controls. TTBK1 immunoreactivity appeared to vary with the level of phospho-tau staining, 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 unlabeled 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.
authors.affiliation: Neuroscience Department, AstraZeneca R&D, Södertälje, Sweden. harald.lund@ki.se
authors.forename: Harald
authors.initials: H
authors.lastname: Lund
authors.forename: Richard F
authors.initials: RF
authors.lastname: Cowburn
authors.forename: Elin
authors.initials: E
authors.lastname: Gustafsson
authors.forename: Kia
authors.initials: K
authors.lastname: Strömberg
authors.forename: Anne
authors.initials: A
authors.lastname: Svensson
authors.forename: Leif
authors.initials: L
authors.lastname: Dahllund
authors.forename: David
authors.initials: D
authors.lastname: Malinowsky
authors.forename: Dan
authors.initials: D
authors.lastname: Sunnemark
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D014162:Transfection; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D016875:tau Proteins; D012694:Serine; C095903:tau-tubulin kinase; D017346:Protein Serine-Threonine Kinases