Dysregulation of Protein Phosphorylation/Dephosphorylation in Alzheimer's Disease: A Therapeutic Target

Studies during the last two decades have provided new insights into the molecular mechanism of Alzheimer's disease (AD). One of the milestone findings in AD research was the demonstration that neurofibrillary degeneration characterized by tau pathology is central to the pathogenesis of AD and other tauopathies and that abnormal hyperphosphorylation of tau is pivotal to neurofibrillary degeneration. This article reviews the recent research advances in tau pathology and the underlying dysregulation of the protein phosphorylation/dephosphorylation system. An updated model of the mechanism of neurofibrillary degeneration is also presented, and a promising therapeutic target to treat AD by correcting dysregulation of protein phosphorylation/dephosphorylation is discussed.

[1]  Fei Liu,et al.  Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation , 2005, The European journal of neuroscience.

[2]  M. Vitek,et al.  Tau is essential to β-amyloid-induced neurotoxicity , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[3]  M. Kirschner,et al.  A protein factor essential for microtubule assembly. , 1975, Proceedings of the National Academy of Sciences of the United States of America.

[4]  S. Feinstein,et al.  Identification of a novel microtubule binding and assembly domain in the developmentally regulated inter-repeat region of tau , 1994, The Journal of cell biology.

[5]  I. Grundke‐Iqbal,et al.  τ 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 , 1998, FEBS letters.

[6]  R. A. Crowther,et al.  Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer's disease , 1989, Neuron.

[7]  Khadija Iqbal,et al.  Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[8]  K. Jellinger,et al.  Accumulation of abnormally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer's disease , 1989, Brain Research.

[9]  Jia-Jia Liu,et al.  Microtubule-associated protein 1B , 2002, The Journal of cell biology.

[10]  R. Kayed,et al.  Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[11]  I. Grundke‐Iqbal,et al.  Aberrant glycosylation modulates phosphorylation of tau by protein kinase A and dephosphorylation of tau by protein phosphatase 2A and 5 , 2002, Neuroscience.

[12]  H. Wiśniewski,et al.  Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[13]  I. Grundke‐Iqbal,et al.  Dephosphorylation of Tau by Protein Phosphatase 5 , 2005, Journal of Biological Chemistry.

[14]  E. Mandelkow,et al.  Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. , 1999, Biochemistry.

[15]  N. Hirokawa,et al.  Tau Proteins: the Molecular Structure and Mode of Binding on Microtubules Materials and Methods Isolation of Tau , 1988 .

[16]  Kenneth S. Kosik,et al.  Developmentally regulated expression of specific tau sequences , 1989, Neuron.

[17]  E. Mandelkow,et al.  Overexpression of Tau Protein Inhibits Kinesin-dependent Trafficking of Vesicles, Mitochondria, and Endoplasmic Reticulum: Implications for Alzheimer's Disease , 1998, The Journal of cell biology.

[18]  L. Tsai,et al.  Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration , 1999, Nature.

[19]  I. Grundke‐Iqbal,et al.  The regulation of phosphorylation of τ in SY5Y neuroblastoma cells: the role of protein phosphatases , 1998, FEBS letters.

[20]  J. Ávila,et al.  Microtubule-associated protein MAP1B showing a fetal phosphorylation pattern is present in sites of neurofibrillary degeneration in brains of Alzheimer's disease patients. , 1994, Brain research. Molecular brain research.

[21]  I. Grundke‐Iqbal,et al.  Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O-GlcNAcylation. , 2006, Journal of Alzheimer's disease : JAD.

[22]  I. Grundke‐Iqbal,et al.  Microtubule associated protein tau binds to double-stranded but not single-stranded DNA , 2003, Cellular and Molecular Life Sciences CMLS.

[23]  S. Rapoport,et al.  Tracking of Alzheimer's disease progression with cerebrospinal fluid tau protein phosphorylated at threonine 231 , 2001, Annals of neurology.

[24]  I. Grundke‐Iqbal,et al.  Role of protein phosphatase‐2A and ‐1 in the regulation of GSK‐3, cdk5 and cdc2 and the phosphorylation of tau in rat forebrain , 2000, FEBS letters.

[25]  M. Kirschner,et al.  Physical and chemical properties of purified tau factor and the role of tau in microtubule assembly. , 1977, Journal of molecular biology.

[26]  Wendy Noble,et al.  Tyrosine 394 Is Phosphorylated in Alzheimer's Paired Helical Filament Tau and in Fetal Tau with c-Abl as the Candidate Tyrosine Kinase , 2005, The Journal of Neuroscience.

[27]  Ping Duan,et al.  Effects of melatonin on wortmannin-induced tau hyperphosphorylation , 2005, Acta Pharmacologica Sinica.

[28]  I. Grundke‐Iqbal,et al.  Hyperphosphorylation and accumulation of neurofilament proteins in Alzheimer disease brain and in okadaic acid‐treated SY5Y cells , 2001, FEBS letters.

[29]  Khadija Iqbal,et al.  Inhibition of PP‐2A upregulates CaMKII in rat forebrain and induces hyperphosphorylation of tau at Ser 262/356 , 2001, FEBS letters.

[30]  R. Neve,et al.  Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. , 1986, Brain research.

[31]  Katharina Buerger,et al.  Differential diagnosis of Alzheimer disease with cerebrospinal fluid levels of tau protein phosphorylated at threonine 231. , 2002, Archives of neurology.

[32]  M. Vitek,et al.  Tau is essential to beta -amyloid-induced neurotoxicity. , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Jian-Zhi Wang,et al.  Melatonin attenuates isoproterenol‐induced protein kinase A overactivation and tau hyperphosphorylation in rat brain , 2004, Journal of pineal research.

[34]  J. Wegiel,et al.  Phosphorylation of Microtubule-associated Protein Tau Is Regulated by Protein Phosphatase 2A in Mammalian Brain , 2000, The Journal of Biological Chemistry.

[35]  S. Yen,et al.  The extent of phosphorylation of fetal tau is comparable to that of PHF-tau from Alzheimer paired helical filaments , 1993, Brain Research.

[36]  R. A. Crowther,et al.  Axonopathy and amyotrophy in mice transgenic for human four-repeat tau protein , 2000, Acta Neuropathologica.

[37]  T. Arendt,et al.  Pseudophosphorylation of tau protein alters its ability for self‐aggregation , 2004, Journal of neurochemistry.

[38]  Hiroyuki Arai,et al.  Phosphorylated tau in human cerebrospinal fluid is a diagnostic marker for Alzheimer's disease , 1999, Neuroscience Letters.

[39]  G. Hart,et al.  O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[40]  I. Grundke‐Iqbal,et al.  Bilateral injection of isoproterenol into hippocampus induces Alzheimer‐like hyperphosphorylation of tau and spatial memory deficit in rat , 2005, FEBS letters.

[41]  W. Markesbery,et al.  Alzheimer's neurofibrillary pathology and the spectrum of cognitive function: Findings from the Nun Study , 2002, Annals of neurology.

[42]  John Q Trojanowski,et al.  Transgenic animal models of tauopathies. , 2005, Biochimica et biophysica acta.

[43]  Khadija Iqbal,et al.  Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. , 1993, The Journal of biological chemistry.

[44]  L. Parnetti,et al.  CSF phosphorylated tau is a possible marker for discriminating Alzheimer's disease from dementia with Lewy bodies , 2001, Neurological Sciences.

[45]  Bradley T. Hyman,et al.  Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease , 1992, Neurology.

[46]  H. Hampel,et al.  Detection of tau phosphorylated at threonine 231 in cerebrospinal fluid of Alzheimer's disease patients , 2000, Neuroscience Letters.

[47]  I. Grundke‐Iqbal,et al.  Tau Becomes a More Favorable Substrate for GSK-3 When It Is Prephosphorylated by PKA in Rat Brain* , 2004, Journal of Biological Chemistry.

[48]  G. Bloom,et al.  Molecular Interactions among Protein Phosphatase 2A, Tau, and Microtubules , 1999, The Journal of Biological Chemistry.

[49]  E. Mandelkow,et al.  RNA stimulates aggregation of microtubule‐associated protein tau into Alzheimer‐like paired helical filaments , 1996, FEBS letters.

[50]  G. Johnson,et al.  Tau phosphorylation in neuronal cell function and dysfunction , 2004, Journal of Cell Science.

[51]  Katharina Buerger,et al.  Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer disease: a comparative cerebrospinal fluid study. , 2004, Archives of general psychiatry.

[52]  I. Grundke‐Iqbal,et al.  Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[53]  B. Winblad,et al.  Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70 S6, similar to that in Alzheimer's disease. , 2003, The American journal of pathology.

[54]  P. Hof,et al.  Phosphorylated serine422 on tau proteins is a pathological epitope found in several diseases with neurofibrillary degeneration , 1999, Acta Neuropathologica.

[55]  Wen-Lang Lin,et al.  Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein , 2000, Nature Genetics.

[56]  G. Glenner,et al.  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. , 1984, Biochemical and biophysical research communications.

[57]  D. Claus,et al.  Myotonic dystrophy: Correlation of clinical symptoms with the size of the CTG trinucleotide repeat , 2004, Journal of Neurology.

[58]  R. Brandt,et al.  Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain , 1995, The Journal of cell biology.

[59]  P. Cohen,et al.  Protein phosphatase 2A is the major enzyme in brain that dephosphorylates tau protein phosphorylated by proline-directed protein kinases or cyclic AMP-dependent protein kinase. , 1995, Journal of neurochemistry.

[60]  D. Dickson,et al.  Alzheimer's disease. A double-labeling immunohistochemical study of senile plaques. , 1988, The American journal of pathology.

[61]  S. Feinstein,et al.  Kinetic stabilization of microtubule dynamics at steady state by tau and microtubule-binding domains of tau. , 1995, Biochemistry.

[62]  J. Cho,et al.  Glycogen synthase kinase 3beta phosphorylates tau at both primed and unprimed sites. Differential impact on microtubule binding. , 2003, The Journal of biological chemistry.

[63]  A Klug,et al.  Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[64]  J. Trojanowski,et al.  A68: a major subunit of paired helical filaments and derivatized forms of normal Tau. , 1991, Science.

[65]  I. Grundke‐Iqbal,et al.  Memantine inhibits and reverses the Alzheimer type abnormal hyperphosphorylation of tau and associated neurodegeneration , 2004, FEBS letters.

[66]  S. Jenkins,et al.  Tau complexes with phospholipase C‐γ in situ , 1998 .

[67]  I. Grundke‐Iqbal,et al.  Brain Levels of Microtubule‐Associated Protein τ Are Elevated in Alzheimer's Disease: A Radioimmuno‐Slot‐Blot Assay for Nanograms of the Protein , 1992, Journal of neurochemistry.

[68]  D. Jung,et al.  Interaction of microtubules and microtubule-associated proteins (MAPs) with rat brain mitochondria. , 1990, The Biochemical journal.

[69]  Qing Tian,et al.  Role of Serine/Threonine Protein Phosphatase in Alzheimer’s Disease , 2002, Neurosignals.

[70]  J M Lee,et al.  A gene expression profile of Alzheimer's disease. , 2001, DNA and cell biology.

[71]  D. Geschwind,et al.  Human Wild-Type Tau Interacts with wingless Pathway Components and Produces Neurofibrillary Pathology in Drosophila , 2002, Neuron.

[72]  J. Lucas,et al.  Spatial learning deficit in transgenic mice that conditionally over‐express GSK‐3β in the brain but do not form tau filaments , 2002, Journal of neurochemistry.

[73]  I. Grundke‐Iqbal,et al.  Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains , 1994, FEBS letters.

[74]  I. Grundke‐Iqbal,et al.  Phosphatase Activity Toward Abnormally Phosphorylated τ: Decrease in Alzheimer Disease Brain , 1995, Journal of neurochemistry.

[75]  G. Hart,et al.  The Microtubule-associated Protein Tau Is Extensively Modified with O-linked N-acetylglucosamine* , 1996, The Journal of Biological Chemistry.

[76]  I. Grundke‐Iqbal,et al.  Up-regulation of inhibitors of protein phosphatase-2A in Alzheimer's disease. , 2005, The American journal of pathology.

[77]  C. Masters,et al.  Amyloid plaque core protein in Alzheimer disease and Down syndrome. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[78]  M. Goedert,et al.  Expression of separate isoforms of human tau protein: correlation with the tau pattern in brain and effects on tubulin polymerization. , 1990, The EMBO journal.

[79]  Alistair Burns,et al.  Observations on the brains of demented old people. B.E. Tomlinson, G. Blessed and M. Roth, Journal of the Neurological Sciences (1970) 11, 205–242; (1968) 7, 331–356 , 1997 .

[80]  G. V. Van Hoesen,et al.  Phosphorylation of Tau by Fyn: Implications for Alzheimer's Disease , 2004, The Journal of Neuroscience.

[81]  B. Winblad,et al.  DEFECTIVE BRAIN MICROTUBULE ASSEMBLY IN ALZHEIMER'S DISEASE , 1986, The Lancet.

[82]  J. Kuret,et al.  C-terminal inhibition of tau assembly in vitro and in Alzheimer's disease. , 2000, Journal of cell science.

[83]  I. Grundke‐Iqbal,et al.  Tau pathology in Alzheimer disease and other tauopathies. , 2005, Biochimica et biophysica acta.

[84]  Alejandra del C. Alonso,et al.  Alzheimer's disease hyperphosphorylated tau sequesters normal tau into tangles of filaments and disassembles microtubules , 1996, Nature Medicine.

[85]  S. Yen,et al.  Disease-related Modifications in Tau Affect the Interaction between Fyn and Tau* , 2005, Journal of Biological Chemistry.

[86]  L. Sternberger,et al.  Aberrant neurofilament phosphorylation in Alzheimer disease. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[87]  Jian-Zhi Wang,et al.  Effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in rat , 2004 .

[88]  W. Netzer,et al.  Overactivation 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 , 2003, Journal of neurochemistry.

[89]  R. Nitsch,et al.  β-Amyloid Induces Paired Helical Filament-like Tau Filaments in Tissue Culture* , 2003, Journal of Biological Chemistry.

[90]  E. Mandelkow,et al.  Phosphorylation of Ser262 strongly reduces binding of tau to microtubules: Distinction between PHF-like immunoreactivity and microtubule binding , 1993, Neuron.

[91]  T. Fath,et al.  Tau-Mediated Cytotoxicity in a Pseudohyperphosphorylation Model of Alzheimer's Disease , 2002, The Journal of Neuroscience.

[92]  A. Carty Comparsion of antihypertensive agents. , 1970, Lancet.

[93]  I. Grundke‐Iqbal,et al.  Levels of nonphosphorylated and phosphorylated tau in cerebrospinal fluid of Alzheimer's disease patients : an ultrasensitive bienzyme-substrate-recycle enzyme-linked immunosorbent assay. , 2002, The American journal of pathology.

[94]  R. Nitsch,et al.  Reduced protein phosphatase 2A activity induces hyperphosphorylation and altered compartmentalization of tau in transgenic mice. , 2001, The Journal of biological chemistry.

[95]  L. Baki,et al.  PS1 activates PI3K thus inhibiting GSK‐3 activity and tau overphosphorylation: effects of FAD mutations , 2004, The EMBO journal.

[96]  N. Hirokawa,et al.  Altered microtubule organization in small-calibre axons of mice lacking tau protein , 1994, Nature.

[97]  Bin Zhang,et al.  Age-Dependent Emergence and Progression of a Tauopathy in Transgenic Mice Overexpressing the Shortest Human Tau Isoform , 1999, Neuron.

[98]  R. Crowther,et al.  Characterization of mAb AP422, a novel phosphorylation‐dependent monoclonal antibody against tau protein , 1996 .

[99]  H. Braak,et al.  Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer's disease. , 2003, The American journal of pathology.

[100]  F. Liu,et al.  Post-translational modifications of tau protein in Alzheimer’s disease , 2005, Journal of Neural Transmission.

[101]  I. Grundke‐Iqbal,et al.  Dephosphorylation of Alzheimer Paired Helical Filaments by Protein Phosphatase-2A and −2B (*) , 1995, The Journal of Biological Chemistry.

[102]  Joachim Herz,et al.  Genetic Modulation of Tau Phosphorylation in the Mouse , 2003, The Journal of Neuroscience.

[103]  M. Goedert,et al.  Protein Phosphatase 2A Is the Major Enzyme in Brain that Dephosphorylates τ Protein Phosphorylated by Proline‐Directed Protein Kinases or Cyclic AMP‐Dependent Protein Kinase , 1995 .

[104]  K. Blennow,et al.  CSF‐Phospho‐tau (181P) as a Promising Marker for Discriminating Alzheimer's Disease from Dementia with Lewy Bodies , 2002 .

[105]  B. Winblad,et al.  Histopathological criteria for progressive dementia disorders: clinical-pathological correlation and classification by multivariate data analysis , 2004, Acta Neuropathologica.

[106]  J. Trojanowski,et al.  Neurodegenerative tauopathies. , 2001, Annual review of neuroscience.

[107]  A. Kakita,et al.  Calpain‐mediated degradation of p35 to p25 in postmortem human and rat brains , 2001, FEBS letters.

[108]  I. Grundke‐Iqbal,et al.  Phosphoprotein Phosphatase Activities in Alzheimer Disease Brain , 1993, Journal of neurochemistry.

[109]  K. Tomizawa,et al.  Truncation and Activation of Calcineurin A by Calpain I in Alzheimer Disease Brain* , 2005, Journal of Biological Chemistry.

[110]  I. Grundke‐Iqbal,et al.  A pool of β‐tubulin is hyperphosphorylated at serine residues in Alzheimer disease brain , 2001, FEBS letters.

[111]  I. Grundke‐Iqbal,et al.  Role of tau phosphorylation by glycogen synthase kinase-3β in the regulation of organelle transport , 2004, Journal of Cell Science.

[112]  G. Hart,et al.  O-Glycosylation of Nuclear and Cytosolic Proteins , 2000, The Journal of Biological Chemistry.

[113]  B. Yoo,et al.  Neurobiology: p25 protein in neurodegeneration , 2001, Nature.

[114]  S. Yen,et al.  Phosphate analysis and dephosphorylation of modified tau associated with paired helical filaments , 1992, Brain Research.

[115]  K. Breen,et al.  The potential role of tau protein O-glycosylation in Alzheimer's disease. , 2004, Journal of Alzheimer's disease : JAD.

[116]  I. Everall,et al.  Rapid Tyrosine Phosphorylation of Neuronal Proteins Including Tau and Focal Adhesion Kinase in Response to Amyloid-β Peptide Exposure: Involvement of Src Family Protein Kinases , 2002, The Journal of Neuroscience.

[117]  N. Cairns,et al.  Tau proteins of alzheimer paired helical filaments: Abnormal phosphorylation of all six brain isoforms , 1992, Neuron.

[118]  P. Seymour,et al.  Tau protein phosphorylation as a therapeutic target in Alzheimer's disease. , 2002, Current topics in medicinal chemistry.

[119]  I. Grundke‐Iqbal,et al.  Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK‐3β , 2002, FEBS letters.

[120]  L. Tsai,et al.  p25 protein in neurodegeneration , 2001 .

[121]  I. Grundke‐Iqbal,et al.  Glycosylation of microtubule–associated protein tau: An abnormal posttranslational modification in Alzheimer's disease , 1996, Nature Medicine.

[122]  P. S. St George-Hyslop,et al.  Brain levels of CDK5 activator p25 are not increased in Alzheimer's or other neurodegenerative diseases with neurofibrillary tangles , 2003, Journal of neurochemistry.

[123]  H. Wiśniewski,et al.  Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. , 1986, The Journal of biological chemistry.

[124]  G. Johnson,et al.  Tau complexes with phospholipase C-gamma in situ. , 1998, Neuroreport.

[125]  H. Okada,et al.  Glycosylation of microtubule-associated protein tau in Alzheimer’s disease brain , 1999, Acta Neuropathologica.

[126]  Jian-Zhi Wang,et al.  Effect of melatonin on calyculin A-induced tau hyperphosphorylation. , 2005, European journal of pharmacology.

[127]  R. Hoffmann,et al.  Unique Alzheimer's disease paired helical filament specific epitopes involve double phosphorylation at specific sites. , 1997, Biochemistry.

[128]  Rachelle Doody,et al.  Memantine in moderate-to-severe Alzheimer's disease. , 2003, The New England journal of medicine.

[129]  A. Delacourte,et al.  Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins--a role in nuclear localization. , 2003, Biochimica et biophysica acta.

[130]  Carl W. Cotman,et al.  Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis , 2003, Science.

[131]  J. Trojanowski,et al.  PP2A mRNA Expression Is Quantitatively Decreased in Alzheimer's Disease Hippocampus , 2001, Experimental Neurology.

[132]  I. Grundke‐Iqbal,et al.  Role of glycosylation in hyperphosphorylation of tau in Alzheimer's disease , 2002, FEBS letters.

[133]  R. Nitsch,et al.  Activation of the ERK and JNK signaling pathways caused by neuron-specific inhibition of PP2A in transgenic mice. , 2003, The American journal of pathology.

[134]  J. Dausset,et al.  Journal of Biomedicine and Biotechnology , 2001, Journal of biomedicine & biotechnology.

[135]  M. Spillantini,et al.  Tau protein in familial and sporadic diseases , 2007, NeuroMolecular Medicine.

[136]  G. Perry,et al.  Formation of aberrant phosphotau fibrillar polymers in neural cultured cells. , 2002, European journal of biochemistry.

[137]  H. Geerts,et al.  Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. , 1999, The American journal of pathology.

[138]  Y. Ihara,et al.  τ in Paired Helical Filaments Is Functionally Distinct from Fetal τ: Assembly Incompetence of Paired Helical Filament‐τ , 1993 .

[139]  Q. Tian,et al.  Activation of glycogen synthase kinase-3 induces Alzheimer-like tau hyperphosphorylation in rat hippocampus slices in culture , 2005, Journal of Neural Transmission.

[140]  R. Martins,et al.  Mutations in the tau gene that cause an increase in three repeat tau and frontotemporal dementia. , 2003, Brain : a journal of neurology.

[141]  H. Braak,et al.  A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads , 2004, Acta Neuropathologica.

[142]  Jian-Zhi Wang,et al.  Melatonin protects SH‐SY5Y neuroblastoma cells from calyculin A‐induced neurofilament impairment and neurotoxicity , 2004, Journal of pineal research.

[143]  I. Grundke‐Iqbal,et al.  Alzheimer paired helical filaments Restoration of the biological activity by dephosphorylation , 1994, FEBS letters.

[144]  Khadija Iqbal,et al.  Interaction of tau isoforms with Alzheimer's disease abnormally hyperphosphorylated tau and in vitro phosphorylation into the disease-like protein. , 2001, The Journal of biological chemistry.

[145]  Qi-Zhang,et al.  Effects of melatonin on wortmannin-induced tau hyperphosphorylation , 2005 .

[146]  G. Bloom,et al.  Regulation of the Phosphorylation State and Microtubule-Binding Activity of Tau by Protein Phosphatase 2A , 1996, Neuron.

[147]  J. Cho,et al.  Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3β (GSK3β) plays a critical role in regulating tau's ability to bind and stabilize microtubules , 2003, Journal of neurochemistry.

[148]  J. Trojanowski,et al.  τ Phosphorylation in Human, Primate, and Rat Brain: Evidence that a Pool of τ Is Highly Phosphorylated In Vivo and Is Rapidly Dephosphorylated In Vitro , 1994, Journal of neurochemistry.

[149]  I. Grundke‐Iqbal,et al.  Promotion of Hyperphosphorylation by Frontotemporal Dementia Tau Mutations* , 2004, Journal of Biological Chemistry.

[150]  R. Hen,et al.  Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. , 2001, The EMBO journal.

[151]  A. Hyman,et al.  Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. , 1992, Molecular biology of the cell.

[152]  G. Lindwall,et al.  Phosphorylation affects the ability of tau protein to promote microtubule assembly. , 1984, The Journal of biological chemistry.

[153]  G. Schellenberg,et al.  Tau is a candidate gene for chromosome 17 frontotemporal dementia , 1998, Annals of neurology.

[154]  Khadija Iqbal,et al.  Abnormal phosphorylation of tau precedes ubiquitination in neurofibrillary pathology of Alzheimer disease , 1991, Brain Research.

[155]  Ronald C. Petersen,et al.  Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 , 1998, Nature.

[156]  René Hen,et al.  Decreased nuclear β‐catenin, tau hyperphosphorylation and neurodegeneration in GSK‐3β conditional transgenic mice , 2001 .

[157]  Katharina Buerger,et al.  Large‐scale, multicenter study of cerebrospinal fluid tau protein phosphorylated at serine 199 for the antemortem diagnosis of Alzheimer's disease , 2001, Annals of neurology.

[158]  J. Trojanowski,et al.  Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau , 1994, Neuron.

[159]  S. Speciale,et al.  Altered Expression Levels of the Protein Phosphatase 2A ABαC Enzyme Are Associated with Alzheimer Disease Pathology , 2004, Journal of neuropathology and experimental neurology.

[160]  Khadija Iqbal,et al.  Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[161]  R. Neve,et al.  The microtubule binding domain of tau protein , 1989, Neuron.

[162]  I. Grundke‐Iqbal,et al.  Potentiation of GSK-3-catalyzed Alzheimer-like phosphorylation of human tau by cdk5 , 1997, Molecular and Cellular Biochemistry.

[163]  J. Rosales,et al.  Controversies over p25 in Alzheimer's disease. , 2002, Journal of Alzheimer's disease : JAD.

[164]  H. Band,et al.  Tau interacts with src-family non-receptor tyrosine kinases. , 1998, Journal of cell science.

[165]  Y. Ihara,et al.  Tau in paired helical filaments is functionally distinct from fetal tau: assembly incompetence of paired helical filament-tau. , 1993, Journal of neurochemistry.

[166]  John Q. Trojanowski,et al.  Abnormal tau phosphorylation at Ser396 in alzheimer's disease recapitulates development and contributes to reduced microtubule binding , 1993, Neuron.

[167]  B. Winblad,et al.  Memantine in severe dementia: results of the 9M‐best study (benefit and efficacy in severly demented patients during treatment with memantine) , 1999, International journal of geriatric psychiatry.

[168]  B. Anderton,et al.  Functional Differences of Tau Isoforms Containing 3 or 4 C-terminal Repeat Regions and the Influence of Oxidative Stress* , 2001, The Journal of Biological Chemistry.