title: S6 kinase phosphorylated at T229 is involved in tau and actin pathologies in Alzheimer's disease.
abstract: The 70-kDa ribosomal protein S6 kinase (S6K), a serine/threonine kinase that modulates the phosphorylation of the 40S ribosomal protein S6, regulates cell cycle progression and is known as a tau kinase in Alzheimer's disease (AD). In AD brains, neurofibrillary tangles (NFTs) have been shown to be positively stained with antibodies against S6K proteins phosphorylated at T389 (pT389-S6K) or T421/S424 (pT421/S424-S6K) by the mammalian target of rapamycin and mitogen-activated protein kinase pathways, respectively. However, there is little information available about S6K proteins directly phosphorylated at T229 (pT229-S6K) by the PI3K-PDK1 pathway. In the present study, we investigated the distribution of pT229-S6K in post mortem human brain tissues from elderly (control) and patients with AD using immnunoblotting and immunohistochemistry. pT229-S6K immunoreactivity was localized to small granular structures in neurons and endothelial cells in control and AD brains. In AD brains, intense pT229-S6K immunoreactivity was detected in 16.3% of AT8-positive NFTs, neuropil threads, and dystrophic neurites in the hippocampus and other vulnerable brain areas. In addition, Hirano bodies were also positive for pT229-S6K but were negative for pT389-S6K or pT421/S424-S6K. The present results indicate that S6K phosphorylation via the PI3K-PD1 pathway is involved in tau pathology in NFTs and abnormal neurites as well as actin pathology in Hirano bodies.
authors.affiliation: Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan.|Rehabilitation Units, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Yuma
authors.initials: Y
authors.lastname: Sonoda
authors.affiliation: Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Japan.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Tooyama
authors.affiliation: Biosignal Research Center, Kobe University, Kobe, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Mukai
authors.affiliation: Department of Medical Rehabilitation, Kobe Gakuin University, Kobe, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Maeda
authors.affiliation: Department of Neuropathology, Tokyo Institute of Psychiatry, Tokyo, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Kawamata
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology*; D001921:Brain / Q000201:enzymology* / Q000473:pathology*; D005260:Female; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000201:enzymology*; D010766:Phosphorylation; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D015398:Signal Transduction; D016875:tau Proteins / Q000378:metabolism
chemical_list: D000199:Actins; C054369:MAPT protein, human; D016875:tau Proteins; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578562:PDPK1 protein, human; D019893:Ribosomal Protein S6 Kinases
keywords: Alzheimer's disease; Hirano body; S6K (70-kDa ribosomal protein S6 kinase); neurofibrillary tangle; phosphorylation