Summary.
Overactivation of protein kinase in the end stage of Alzheimer’s disease brain has not been established. The purpose of the present study was to explore the possible mechanism for protein kinases in leading to Alzheimer-like tau hyperphosphorylation. We found that incubation of N2a/tau441 with forskolin, a specific activator of cAMP-dependent protein kinase (PKA), induced an increased phosphorylation level of tau at both PKA and non-PKA sites in a dose- and time-dependent manner, and the hyperphosphorylation of tau was positively correlated with the elevation of PKA activity. When the cells were transitorily incubated with forskolin, a temporary activation of PKA with a sustained and almost equally graded tau hyperphosphorylation at some non-PKA sites was observed. In either case, the activity of glycogen synthase kinase-3 (GSK-3) was not changed. It is suggested that only transitory activation of PKA in early stage of Alzheimer disease may result in a sustained tau hyperphosphorylation at multiple sites, implying a new mechanism to Alzheimer-like tau hyperphosphorylation.
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References
EY Adashi CE Resnick (1986) ArticleTitle3′,5′-cyclic adenosine monophosphate as an intracellular second messenger of luteinizing hormone: application of the forskolin criteria J Cell Biochem 31 217–228 Occurrence Handle2484681 Occurrence Handle1:CAS:528:DyaL28XltVyqu7k%3D Occurrence Handle10.1002/jcb.240310304
J Avila JJ Lucas M Perez F Hernandez (2004) ArticleTitleRole of tau protein in both physiological and pathological conditions Physiol Rev 84 361–384 Occurrence Handle15044677 Occurrence Handle1:CAS:528:DC%2BD2cXjtlCktL0%3D Occurrence Handle10.1152/physrev.00024.2003
M Bennecib CX Gong I Grundke-Iqbal K Iqbal (2000) ArticleTitleRole of protein phosphatase-2A and -1 in the regulation of GSK-3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain FEBS Lett 485 87–93 Occurrence Handle11086171 Occurrence Handle1:CAS:528:DC%2BD3cXot12qsbg%3D Occurrence Handle10.1016/S0014-5793(00)02203-1
RV Bhat SL Budd Haeberlein J Avila (2004) ArticleTitleGlycogen synthase kinase 3: a drug target for CNS therapies J Neurochem 89 1313–1317 Occurrence Handle15189333 Occurrence Handle1:CAS:528:DC%2BD2cXlsVOhtLo%3D Occurrence Handle10.1111/j.1471-4159.2004.02422.x
J Biernat EM Mandelkow C Schroter B Lichtenberg-Kraag B Steiner B Berling H Meyer M Mercken A Vandermeeren M Goedert et al. (1992) ArticleTitleThe switch of tau protein to an Alzheimer-like state includes the phosphorylation of two serine-proline motifs upstream of the microtubule binding region EMBO J 11 1593–1597 Occurrence Handle1563356 Occurrence Handle1:CAS:528:DyaK38Xitleitrk%3D
E Braak H Braak EM Mandelkow (1994) ArticleTitleA sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads Acta Neuropathol (Berl) 87 554–567 Occurrence Handle1:STN:280:DyaK2cznvVyisQ%3D%3D
JE Casnellie (1991) ArticleTitleAssay of protein kinases using peptides with basic residues for phosphocellulose binding Meth Enzymol 200 115–120 Occurrence Handle1956315 Occurrence Handle1:CAS:528:DyaK3MXmsFSksLc%3D Occurrence Handle10.1016/0076-6879(91)00133-H
CX Gong F Liu I Grundke-Iqbal K Iqbal (2005) ArticleTitlePost-translational modifications of tau protein in Alzheimer’s disease J Neural Transm 112 813–838 Occurrence Handle15517432 Occurrence Handle1:CAS:528:DC%2BD2MXjvVSqt7o%3D Occurrence Handle10.1007/s00702-004-0221-0
JA Greenwood CW Scott RC Spreen CB Caputo GV Johnson (1994) ArticleTitleCasein kinase II preferentially phosphorylates human tau isoforms containing an amino-terminal insert. Identification of threonine 39 as the primary phosphate acceptor J Biol Chem 269 4373–4380 Occurrence Handle8308007 Occurrence Handle1:CAS:528:DyaK2cXhvVGqsbs%3D
I Grundke-Iqbal K Iqbal YC Tung M Quinlan HM Wisniewski LI Binder (1986) ArticleTitleAbnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology Proc Natl Acad Sci USA 83 4913–4917 Occurrence Handle3088567 Occurrence Handle1:CAS:528:DyaL28XksFyqtrg%3D Occurrence Handle10.1073/pnas.83.13.4913
K Iqbal I Grundke-Iqbal T Zaidi PA Merz GY Wen SS Shaikh HM Wisniewski I Alafuzoff B Winblad (1986) ArticleTitleDefective brain microtubule assembly in Alzheimer’s disease Lancet ii 421–426 Occurrence Handle10.1016/S0140-6736(86)92134-3
K Iqbal A del C Alonso E El-Akkad C-X Gong N Haque S Khatoon JJ Pei I Tsujio JZ Wang I Grundke-Iqbal (2002) ArticleTitleSignificance and mechanism of Alzheimer neurofibrillary degeneration and therapeutic targets to inhibit this lesion J Mol Neurosci 19 95–99 Occurrence Handle12212801 Occurrence Handle1:CAS:528:DC%2BD38XmvFCqur0%3D
BE Kemp DJ Graves E Benjamini EG Krebs (1977) ArticleTitleRole of multiple basic residues in determining the substrate specificity of cyclic AMP-dependent protein kinase J Biol Chem 252 4888–4894 Occurrence Handle194899 Occurrence Handle1:CAS:528:DyaE2sXlt12gu7Y%3D
E Kopke YC Tung S Shaikh AC Alonso K Iqbal I Grundke-Iqbal (1993) ArticleTitleMicrotubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease J Biol Chem 268 24374–24384 Occurrence Handle8226987 Occurrence Handle1:CAS:528:DyaK3sXmtVWisro%3D
KS Kosik (1992) ArticleTitleAlzheimer’s disease: a cell biological perspective Science 256 780–783 Occurrence Handle1589757 Occurrence Handle1:CAS:528:DyaK38XktVGitL4%3D
H Ksiezak-Reding LI Binder SH Yen (1988) ArticleTitleImmunochemical and biochemical characterization of tau proteins in normal and Alzheimer’s disease brains with Alz 50 and Tau-1 J Biol Chem 263 7948–7953 Occurrence Handle3131334 Occurrence Handle1:CAS:528:DyaL1cXkt1WitLk%3D
H Ksiezak-Reding LI Binder SH Yen (1990) ArticleTitleAlzheimer disease proteins (A68) share epitopes with tau but show distinct biochemical properties J Neurosci Res 25 420–430 Occurrence Handle1691309 Occurrence Handle1:CAS:528:DyaK3cXhvFKitLw%3D Occurrence Handle10.1002/jnr.490250320
LF Lau JB Schachter PA Seymour MA Sanner (2002) ArticleTitleTau protein phosphorylation as a therapeutic target in Alzheimer’s disease Curr Top Med Chem 2 395–415 Occurrence Handle11966463 Occurrence Handle1:CAS:528:DC%2BD38Xjt1eksLs%3D Occurrence Handle10.2174/1568026024607526
A Laurenza EM Sutkowski KB Seamon (1989) ArticleTitleForskolin: a specific stimulator of adenylyl cyclase or a diterpene with multiple sites of action? Trends Pharmacol Sci 10 442–447 Occurrence Handle2692256 Occurrence Handle1:CAS:528:DyaK3cXhsFyntA%3D%3D Occurrence Handle10.1016/S0165-6147(89)80008-2
VM Lee BJ Balin L Otvos SuffixJr JQ Trojanowski (1991) ArticleTitleA68: a major subunit of paired helical filaments and derivatized forms of normal Tau Science 251 675–678 Occurrence Handle1899488 Occurrence Handle1:CAS:528:DyaK3MXhsVSqs7k%3D
SJ Liu AH Zhang HL Li Q Wang HM Deng WJ Netzer H Xu JZ Wang (2003) ArticleTitleOveractivation of glycogen synthase kinase-3 by inhibition of phosphoinositol-3 kinase and protein kinase C leads to hyperphosphorylation of tau and impairment of spatial memory J Neurochem 87 1333–1344 Occurrence Handle14713290 Occurrence Handle1:CAS:528:DC%2BD2cXit1Kq Occurrence Handle10.1046/j.1471-4159.2003.02070.x
SJ Liu JY Zhang HL Li ZY Fang Q Wang HM Deng CX Gong I Grundke-Iqbal K Iqbal JZ Wang (2004) ArticleTitleTau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain J Biol Chem 279 50078–50088 Occurrence Handle15375165 Occurrence Handle1:CAS:528:DC%2BD2cXhtVWjs7vP Occurrence Handle10.1074/jbc.M406109200
M Morishima-Kawashima M Hasegawa K Takio M Suzuki H Yoshida A Watanabe K Titani Y Ihara (1995) ArticleTitleHyperphosphorylation of tau in PHF Neurobiol Aging 16 365–380 Occurrence Handle7566346 Occurrence Handle1:CAS:528:DyaK2MXmsVKgsLw%3D Occurrence Handle10.1016/0197-4580(95)00027-C
JJ Pei T Tanaka YC Tung E Braak K Iqbal I Grundke-Iqbal (1997) ArticleTitleDistribution, levels, and activity of glycogen synthase kinase-3 in the Alzheimer disease brain J Neuropathol Exp Neurol 56 70–78 Occurrence Handle8990130 Occurrence Handle1:STN:280:DyaK2s7ksVelsQ%3D%3D
TJ Singh T Zaidi I Grundke-Iqbal K Iqbal (1996) ArticleTitleNon-proline-dependent protein kinases phosphorylate several sites found in tau from Alzheimer disease brain Mol Cell Biochem 154 143–151 Occurrence Handle8717428 Occurrence Handle1:CAS:528:DyaK28XhtVyku7Y%3D Occurrence Handle10.1007/BF00226782
L Sun SY Liu XW Zhou XC Wang R Liu Q Wang JZ Wang (2003) ArticleTitleInhibition of protein phosphatase 2A- and protein phosphatase 1-induced tau hyperphosphorylation and impairment of spatial memory retention in rats Neurosci 118 1175–1182 Occurrence Handle1:CAS:528:DC%2BD3sXjsVejsL0%3D Occurrence Handle10.1016/S0306-4522(02)00697-8
L Sun X Wang S Liu Q Wang J Wang M Bennecib CX Gong A Sengupta I Grundke-Iqbal K Iqbal (2005) ArticleTitleBilateral injection of isoproterenol into hippocampus induces Alzheimer-like hyperphosphorylation of tau and spatial memory deficit in rat FEBS Lett 579 251–258 Occurrence Handle15620722 Occurrence Handle1:CAS:528:DC%2BD2cXhtFGht7nE Occurrence Handle10.1016/j.febslet.2004.11.083
T Tanaka J Zhong K Iqbal E Trenkner I Grundke-Iqbal (1998) ArticleTitleThe regulation of phosphorylation of tau in SY5Y neuroblastoma cells: the role of protein phosphatases FEBS Lett 426 248–254 Occurrence Handle9599018 Occurrence Handle1:CAS:528:DyaK1cXisFalsrw%3D Occurrence Handle10.1016/S0014-5793(98)00346-9
M Tolnay A Probst (1999) ArticleTitleTau protein pathology in Alzheimer’s disease and related disorders Neuropathol Appl Neurobiol 25 171–187 Occurrence Handle10417659 Occurrence Handle1:CAS:528:DyaK1MXltFOis7s%3D Occurrence Handle10.1046/j.1365-2990.1999.00182.x
I Tsujio T Tanaka T Kudo T Nishikawa K Shinozaki I Grundke-Iqbal K Iqbal M Takeda (2000) ArticleTitleInactivation of glycogen synthase kinase-3 by protein kinase C delta: implications for regulation of tau phosphorylation FEBS Lett 469 111–117 Occurrence Handle10708767 Occurrence Handle1:CAS:528:DC%2BD3cXhsFGrt74%3D Occurrence Handle10.1016/S0014-5793(00)01234-5
JZ Wang Q Wu A Smith I Grundke-Iqbal K Iqbal (1998) ArticleTitleTau is phosphorylated by GSK-3 at several sites found in Alzheimer disease and its biological activity markedly inhibited only after it is prephosphorylated by A-kinase FEBS Lett 436 28–34 Occurrence Handle9771888 Occurrence Handle1:CAS:528:DyaK1cXmt1emurY%3D Occurrence Handle10.1016/S0014-5793(98)01090-4
XC Wang ZH Hu XW Tang YG Wu JZ Wang (2004) ArticleTitleCorrelation of Alzheimer-like tau abnormal hyperphosphorylation and fMRI BOLD signal intensity J Curr Alz Res 1 143–145 Occurrence Handle1:CAS:528:DC%2BD2cXjvF2jtL8%3D Occurrence Handle10.2174/1567205043332216
MD Weingarten AH Lockwood SY Hwo MW Kirschner (1975) ArticleTitleA protein factor essential for microtubule assembly Proc Natl Acad Sci USA 72 1858–1862 Occurrence Handle1057175 Occurrence Handle1:CAS:528:DyaE2MXkt1ersbw%3D Occurrence Handle10.1073/pnas.72.5.1858
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Zhang, Y., Li, HL., Wang, DL. et al. A transitory activation of protein kinase-A induces a sustained tau hyperphosphorylation at multiple sites in N2a cells-imply a new mechanism in Alzheimer pathology. J Neural Transm 113, 1487–1497 (2006). https://doi.org/10.1007/s00702-005-0421-2
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DOI: https://doi.org/10.1007/s00702-005-0421-2