Key points are not available for this paper at this time.
Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease (AD) brain. Starvation of adult mice induces tau hyperphosphorylation at many paired helical filaments sites and with a similar regional selectivity as those in AD, suggesting that a common mechanism may be mobilized. Here we investigated the mechanism of starvation-induced tau hyperphosphorylation in terms of tau kinases and Ser/Thr protein phosphatases (PP), and the results were compared with those reported in AD brain. During starvation, tau hyperphosphorylation at specific epitopes was accompanied by decreases in tau protein kinase I/glycogen synthase kinase 3β (TPKI/GSK3β), cyclin-dependent kinase 5 (cdk5), and PP2A activities toward tau. These results demonstrate that the activation of TPKI/GSK3β and cdk5 is not necessary to obtain hyperphosphorylated tau in vivo, and indicate that inhibition of PP2A is likely the dominant factor in inducing tau hyperphosphorylation in the starved mouse, overriding the inhibition of key tau kinases such as TPKI/GSK3β and cdk5. Furthermore, these data give strong support to the hypothesis that PP2A is important for the regulation of tau phosphorylation in the adult brain, and provide in vivo evidence in support of a central role of PP2A in tau hyperphosphorylation in AD. Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease (AD) brain. Starvation of adult mice induces tau hyperphosphorylation at many paired helical filaments sites and with a similar regional selectivity as those in AD, suggesting that a common mechanism may be mobilized. Here we investigated the mechanism of starvation-induced tau hyperphosphorylation in terms of tau kinases and Ser/Thr protein phosphatases (PP), and the results were compared with those reported in AD brain. During starvation, tau hyperphosphorylation at specific epitopes was accompanied by decreases in tau protein kinase I/glycogen synthase kinase 3β (TPKI/GSK3β), cyclin-dependent kinase 5 (cdk5), and PP2A activities toward tau. These results demonstrate that the activation of TPKI/GSK3β and cdk5 is not necessary to obtain hyperphosphorylated tau in vivo, and indicate that inhibition of PP2A is likely the dominant factor in inducing tau hyperphosphorylation in the starved mouse, overriding the inhibition of key tau kinases such as TPKI/GSK3β and cdk5. Furthermore, these data give strong support to the hypothesis that PP2A is important for the regulation of tau phosphorylation in the adult brain, and provide in vivo evidence in support of a central role of PP2A in tau hyperphosphorylation in AD. Alzheimer's disease amyloid β calcium/calmodulin-dependent protein kinase II cyclin-dependent kinase 5 glycogen synthase kinase 3 c-Jun N-terminal kinase kinase activity buffer mitogen-activated protein kinase/extracellular signal-regulated kinase okadaic acid phospho- polyacrylamide gel electrophoresis paired helical filaments cAMP-dependent protein kinase A protein kinase B phenylmethylsulfonyl fluoride serine/threonine protein phosphatases 2A, 2B, 2C), protein phosphatase (1, 2A, 2B, 2C) 2Ac, 2Bc), protein phosphatase (1, 2A, 2B) catalytic subunit phosphoserine phosphothreonine radioimmune precipitation assay tau protein kinase I tau protein kinase II 4-morpholinoethanesulfonic acid Alzheimer's disease (AD)1 is a neurodegenerative disorder characterized by the presence of two histopathological hallmarks called senile plaques and neurofibrillary tangles. The former are deposits of the β-amyloid peptide (Aβ) (1Selkoe D.J. 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Fujita, manuscript in preparation.2Y. Okawa, K. Ishiguro, and S. C. Fujita, manuscript in preparation. (14Korneyev A. Binder L. Bernardis J. Neurosci. Lett. 1995; 191: 19-22Crossref PubMed Scopus (51) Google Scholar), heat-shock (15Papasozomenos S.C. J. Neurochem. 1996; 66: 1140-1149Crossref PubMed Scopus (36) Google Scholar), or starvation (16Yanagisawa M. Planel E. Ishiguro K. Fujita S.C. FEBS Lett. 1999; 461: 329-333Crossref PubMed Scopus (109) Google Scholar). Starvation induces decreases in circulating glucose, insulin, and leptin, and increases in corticosterone (17Ahima R.S. Prabakaran D. Mantzoros C. Qu D. Lowell B. Maratos-Flier E. Flier J.S. Nature. 1996; 382: 250-252Crossref PubMed Scopus (2668) Google Scholar), and results in a large decrease of in many of the brain J. R. Brain Res. PubMed Scopus Google Scholar). is with of the brain of and AD S. J. Med. 1995; Google Scholar, K. D. S. D. N. J. Med. 1996; PubMed Scopus Google Scholar), and is by as not in the of AD S. K. J. 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These results demonstrate that the activation of TPKI/GSK3β and cdk5 is not necessary to obtain hyperphosphorylated tau in vivo, and indicate that tau hyperphosphorylation in the starved a mechanism in PP2A inhibition a dominant overriding the inhibition of key tau kinases such as TPKI/GSK3β and cdk5. to mice were in with to was for to 3 mice were to was and the was were to the by the and of the of were by and were from in The were and in of from buffer J. Biol. Chem. Full Text PDF PubMed Google acid phenylmethylsulfonyl fluoride and The were in water for 5 for at at and the protein of the was with the to in buffer as of protein to in the for data not were by gel and to and K. K. M. J. Uchida T. K. Neurosci. Lett. 1995; PubMed Scopus Google to tau phosphorylated at Ishiguro K. Uchida T. A. K. 1996; PubMed Scopus Google Scholar), and the of and T. Ishiguro K. J. M. S. K. FEBS Lett. 1994; PubMed Scopus Google Scholar, S. Ishiguro K. A. M. M. K. Uchida T. 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Res. 1993; PubMed Scopus Google were and were to with and and were from The were with or with and The with the or from were a of of the results was by of was by the of In the the and indicate with and were of 3 mice of and 5 with of and mice of 3 and were with of of to were of at The mice were in the of and were and as were in 5 of buffer of and of okadaic for at and and the protein of the was was at of brain were with of or to or to the in of buffer 3 of and okadaic and for at 3 with and with kinase activity buffer okadaic the were in of activity was by phosphorylation of of of kinases in were with of and tau, and at for or The was by of buffer and for 5 of were by and with as phosphatase of buffer of was to of tau phosphorylation tau, okadaic and and for at of of of tau, as by a assay not The was by for 5 by for at and of acid the was for and for at and The was 3 with in the of buffer 5 as and at of buffer 5 to of activity was by decrease in phosphorylation of tau by the brain as by with were in 5 of phosphatase buffer of and from Gong C.X. 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These were largely of was to the to of the were in 5 of and the for at and The were by and kinase of protein was for for and and for were with or to phosphatase and with of or adult mice were starved for to 3 and were for to of of these mice were by with to protein kinases and phosphatases (16Yanagisawa M. Planel E. Ishiguro K. Fujita S.C. FEBS Lett. 1999; 461: 329-333Crossref PubMed Scopus (109) Google Scholar), tau phosphorylation and by and The two of and are by and a at the acid J. PubMed Scopus Google Scholar). TPKI/GSK3β is a protein kinase for tau hyperphosphorylation in AD (11Imahori K. Uchida T. J. Biochem. (Tokyo). 1997; 121: 179-188PubMed Google Scholar). tau at PHF sites and K. K. M. J. Uchida T. K. Neurosci. Lett. 1995; PubMed Scopus Google of to the tau M. Jakes R. D. Neuron. Full Text PDF PubMed Scopus Google can sites in with kinases J.Z. A. Grundke-Iqbal I. Iqbal K. FEBS Lett. PubMed Scopus Google Scholar). 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Neurochem. 1997; PubMed Scopus Google Scholar), starvation and of starvation were not from These indicate that, starvation, is TPKI/GSK3β is of tau and protein kinases changes in kinase and in the of normal starvation for or 3 starvation for by for or an of and were and the results are as of the are as and indicate from with and of these of mice 3 or to similar and TPKI/GSK3β of of or a from an starved and were not and of and mice and of for 3 and were the were and tau and TPKI/GSK3β were the results are as of the are as and indicate from with of these of mice or to similar of phosphatase catalytic changes in phosphatase catalytic in the of normal starvation for or 3 starvation for by for or to an of and were and the results are as of the are as from with of these of mice 3 or to similar Tau protein, as with in mice as a strong at and a at with a and of starvation, the the at and These tau phosphorylation M. Neuron. Full Text PDF PubMed Scopus Google were not accompanied by changes in tau protein of or catalytic of not changes that with tau phosphorylation Tau protein kinase II is a of a cdk5 catalytic subunit and a subunit from T. Ishiguro K. J. M. S. K. FEBS Lett. 1994; PubMed Scopus Google Scholar, I. T. E. Nature. 1994; PubMed Scopus Google Scholar). tau in vitro at PHF sites and K. K. M. J. Uchida T. K. Neurosci. Lett. 1995; PubMed Scopus Google Scholar). not starvation and a starvation, by a decrease in and the of two at and are likely to be of the to its and the and The of was starvation, the protein of tau or the kinases not for cdk5 a by a starvation a in TPKI/GSK3β the role of in tau hyperphosphorylation was with an of tau phosphorylation by in vitro and in vivo M. Lee V.M. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, J. J. 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Furthermore, these data vivo evidence in support of a central role of PP2A in tau hyperphosphorylation in AD, and the that in the of activity in AD brain, normal of activity are for the hyperphosphorylation of tau at many PHF to of and of mice of and of physiological and of molecules or conditions that may the of tau phosphorylation and lead to PHF that in for those at a kinase may not be and that those that the of the of protein kinases and phosphatases as a to be R. Okawa, and for
Planel et al. (Sat,) studied this question.