title: The Abundance of Nonphosphorylated Tau in Mouse and Human Tauopathy Brains Revealed by the Use of Phos-Tag Method.
abstract: Tauopathies are neurodegenerative diseases characterized by aggregates of hyperphosphorylated tau. Previous studies have identified many disease-related phosphorylation sites on tau. However, it is not understood how tau is hyperphosphorylated and what extent these sites are phosphorylated in both diseased and normal brains. Most previous studies have used phospho-specific antibodies to analyze tau phosphorylation. These results are useful but do not provide information about nonphosphorylated tau. Here, we applied the method of Phos-tag SDS-PAGE, in which phosphorylated tau was separated from nonphosphorylated tau in vivo. Among heterogeneously phosphorylated tau species in adult mouse brains, the nonphosphorylated 0N4R isoform was detected most abundantly. In contrast, perinatal tau and tau in cold water-stressed mice were all phosphorylated with a similar extent of phosphorylation. In normal elderly human brains, nonphosphorylated 0N3R and 0N4R tau were most abundant. A slightly higher phosphorylation of tau, which may represent the early step of hyperphosphorylation, was increased in Alzheimer disease patients at Braak stage V. Tau with this phosphorylation state was pelleted by centrifugation, and sarkosyl-soluble tau in either Alzheimer disease or corticobasal degeneration brains showed phosphorylation profiles similar to tau in normal human brain, suggesting that hyperphosphorylation occurs in aggregated tau. These results indicate that tau molecules are present in multiple phosphorylation states in vivo, and nonphosphorylated forms are highly expressed among them.
authors.affiliation: Department of Biological Sciences, Laboratory of Molecular Neuroscience, Tokyo Metropolitan University, Hachioji, Tokyo, Japan. Electronic address: kimura-taeko@tmu.ac.jp.
authors.forename: Taeko
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hatsuta
authors.affiliation: Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Masuda-Suzukake
authors.affiliation: Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hosokawa
authors.affiliation: Department of Neurology, Graduate School of Medicine, Juntendo University, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Ishiguro
authors.affiliation: Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Itabashi, Tokyo, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Murayama
authors.affiliation: Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Setagaya, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Department of Biological Sciences, Laboratory of Molecular Neuroscience, Tokyo Metropolitan University, Hachioji, Tokyo, Japan. Electronic address: hisanaga-shinichi@tmu.ac.jp.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Hisanaga
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D016875:tau Proteins