Developmental Changes in τ Phosphorylation: Fetal τ Is Transiently Phosphorylated in a Manner Similar to Paired Helical Filament‐τ Characteristic of Alzheimer's Disease

Rat and human fetal brain τ were probed with a panel of monoclonal antibodies (tau‐1, AT8, 8D8, RT97, SMI31, SMI34) that distinguish between paired helical filament (PHF)‐τ of Alzheimer's disease and normal adult brain τ. These antibodies discriminate between normal and PHF‐τ because their epitopes are phosphorylated in PHF‐τ. Although only one molecular isoform of τ was shown to be expressed in fetal brain, two fetal τ species could be distinguished on sodium dodecyl sulfate‐polyacrylamide gel electrophoresis and the slower migrating species was recognized by all of the PHF‐τ‐specific antibodies. Moreover, this immunoreactivity was shown to be phosphorylation dependent. Our observations suggest that the abnormal phosphorylation of τ in Alzheimer's disease may be the result of reactivation of pathways governing the phosphorylation of τ in the developing brain.

[1]  J. Brion,et al.  Neurofilament Monoclonal Antibodies RT97 and 8D8 Recognize Different Modified Epitopes in Paired Helical Filament‐τ in Alzheimer's Disease , 1993, Journal of neurochemistry.

[2]  J. Woodgett,et al.  Glycogen synthase kinase-3 induces Alzheimer's disease-like phosphorylation of tau: Generation of paired helical filament epitopes and neuronal localisation of the kinase , 1992, Neuroscience Letters.

[3]  E. Mandelkow,et al.  The Alzheimer‐like phosphorylation of tau protein reduces microtubule binding and involves Ser‐Pro and Thr‐Pro motifs , 1992, FEBS letters.

[4]  E. Mandelkow,et al.  Phosphorylation-dependent epitopes of neurofilament antibodies on tau protein and relationship with Alzheimer tau. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[5]  G. Drewes,et al.  Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer‐like state. , 1992, The EMBO journal.

[6]  R. Liem,et al.  Primary structure of high molecular weight tau present in the peripheral nervous system. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[7]  K. Titani,et al.  Fetal‐Type Phosphorylation of the τ in Paired Helical Filaments , 1992 .

[8]  E. Mandelkow,et al.  The switch of tau protein to an Alzheimer‐like state includes the phosphorylation of two serine‐proline motifs upstream of the microtubule binding region. , 1992, The EMBO journal.

[9]  R. Crowther,et al.  Cloning of a big tau microtubule-associated protein characteristic of the peripheral nervous system. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

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

[11]  P. Davies,et al.  Hydrofluoric acid-treated tau PHF proteins display the same biochemical properties as normal tau. , 1992, The Journal of biological chemistry.

[12]  G. Innocenti,et al.  Differential Distribution of Tau Proteins in Developing Cat Cerebral Cortex and Corpus Callosum , 1991, The European journal of neuroscience.

[13]  HM Roder,et al.  Two novel kinases phosphorylate tau and the KSP site of heavy neurofilament subunits in high stoichiometric ratios , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[14]  D. Hanger,et al.  A68 proteins in Alzheimer's disease are composed of several tau isoforms in a phosphorylated state which affects their electrophoretic mobilities. , 1991, The Biochemical journal.

[15]  K. Kosik,et al.  Overexpression of tau in a nonneuronal cell induces long cellular processes , 1991, The Journal of cell biology.

[16]  K. Imahori,et al.  A serine/threonine proline kinase activity is included in the tau protein kinase fraction forming a paired helical filament epitope , 1991, Neuroscience Letters.

[17]  N. Cairns,et al.  Tau in Alzheimer's disease and Down's syndrome is insoluble and abnormally phosphorylated. , 1991, The Biochemical journal.

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

[19]  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.

[20]  E. Stopa,et al.  Basic fibroblast growth factor in Alzheimer's disease. , 1990, Biochemical and biophysical research communications.

[21]  M. Hasegawa,et al.  Immunochemical evidence that fragments of phosphorylated MAP5 (MAP1B) are bound to neurofibrillary tangles in Alzheimer's disease , 1990, Neuron.

[22]  M. Coleman,et al.  Phosphate‐Dependent Monoclonal Antibodies to Neurofilaments and Alzheimer Neurofibrillary Tangles Recognize a Synthetic Phosphopeptide , 1990, Journal of neurochemistry.

[23]  S. Yen,et al.  Mapping of the Alz 50 epitope in microtubule‐associated proteins tau , 1990, Journal of neuroscience research.

[24]  K. Kosik,et al.  Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons , 1990, Nature.

[25]  K. Kosik,et al.  Microtubular reorganization and dendritic growth response in alzheimer's disease , 1989, Annals of neurology.

[26]  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.

[27]  N. Hirokawa,et al.  Expression of multiple tau isoforms and microtubule bundle formation in fibroblasts transfected with a single tau cDNA , 1989, The Journal of cell biology.

[28]  G. Cole,et al.  Amyloid beta protein precursor is a mitogen. , 1989, Biochemical and biophysical research communications.

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

[30]  A. Himmler.  Structure of the bovine tau gene: alternatively spliced transcripts generate a protein family , 1989, Molecular and cellular biology.

[31]  R. Crowther,et al.  Cloning and sequencing of the cDNA encoding an isoform of microtubule‐associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain. , 1989, The EMBO journal.

[32]  J. Wood,et al.  Differential sensitivity of the microtubule-associated protein, tau, in Alzheimer's disease tissue to formalin fixation. , 1988, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[33]  Y. Ihara.  Massive somatodendritic sprouting of cortical neurons in Alzheimer's disease , 1988, Brain Research.

[34]  J. Walker,et al.  Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[35]  J. Walker,et al.  Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[36]  J. Brion,et al.  Both adult and juvenile tau microtubule-associated proteins are axon specific in the developing and adult rat cerebellum , 1988, Neuroscience.

[37]  Y. Ihara,et al.  Alzheimer's disease brain extract stimulates the survival of cerebral cortical neurons from neonatal rats. , 1988, Biochemical and biophysical research communications.

[38]  J. Baudier,et al.  Phosphorylation of tau proteins to a state like that in Alzheimer's brain is catalyzed by a calcium/calmodulin-dependent kinase and modulated by phospholipids. , 1987, The Journal of biological chemistry.

[39]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[40]  A. Delacourte,et al.  Alzheimer's disease: Tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments , 1986, Journal of the Neurological Sciences.

[41]  M. Kirschner,et al.  Tau protein function in living cells , 1986, The Journal of cell biology.

[42]  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.

[43]  S. Mirra,et al.  Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal microtubule-associated protein tau (tau) , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[44]  D. Selkoe,et al.  Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

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

[46]  Y. Ihara,et al.  One of the antigenic determinants of paired helical filaments is related to tau protein. , 1986, Journal of biochemistry.

[47]  M. Haugh,et al.  Alzheimer's paired helical filaments share epitopes with neurofilament side arms. , 1986, The EMBO journal.

[48]  A. Frankfurter,et al.  The distribution of tau in the mammalian central nervous system , 1985, The Journal of cell biology.

[49]  J. Nunez,et al.  Immunological characterization of microtubule‐associated proteins specific for the immature brain , 1985, FEBS letters.

[50]  G. Lindwall,et al.  The purification of tau protein and the occurrence of two phosphorylation states of tau in brain. , 1984, The Journal of biological chemistry.

[51]  J. Francon,et al.  Heterogeneity of microtubule-associated proteins and brain development. , 1982, European journal of biochemistry.

[52]  J. Ulrich,et al.  Monoclonal antibodies show that neurofibrillary tangles and neurofilaments share antigenic determinants , 1982, Nature.

[53]  M. Kirschner,et al.  Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. , 1977, Journal of molecular biology.

[54]  C. Cantor,et al.  Microtubule assembly in the absence of added nucleotides. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[55]  D. Hanger,et al.  Tau in Alzheimer neurofibrillary tangles. N- and C-terminal regions are differentially associated with paired helical filaments and the location of a putative abnormal phosphorylation site. , 1991, The Biochemical journal.