Roles of tau protein in health and disease

Tau is well established as a microtubule-associated protein in neurons. However, under pathological conditions, aberrant assembly of tau into insoluble aggregates is accompanied by synaptic dysfunction and neural cell death in a range of neurodegenerative disorders, collectively referred to as tauopathies. Recent advances in our understanding of the multiple functions and different locations of tau inside and outside neurons have revealed novel insights into its importance in a diverse range of molecular pathways including cell signalling, synaptic plasticity, and regulation of genomic stability. The present review describes the physiological and pathophysiological properties of tau and how these relate to its distribution and functions in neurons. We highlight the post-translational modifications of tau, which are pivotal in defining and modulating tau localisation and its roles in health and disease. We include discussion of other pathologically relevant changes in tau, including mutation and aggregation, and how these aspects impinge on the propensity of tau to propagate, and potentially drive neuronal loss, in diseased brain. Finally, we describe the cascade of pathological events that may be driven by tau dysfunction, including impaired axonal transport, alterations in synapse and mitochondrial function, activation of the unfolded protein response and defective protein degradation. It is important to fully understand the range of neuronal functions attributed to tau, since this will provide vital information on its involvement in the development and pathogenesis of disease. Such knowledge will enable determination of which critical molecular pathways should be targeted by potential therapeutic agents developed for the treatment of tauopathies.

[1]  J. Ávila,et al.  Tau Protein and Adult Hippocampal Neurogenesis , 2012, Front. Neurosci..

[2]  A. Hill,et al.  Extracellular Vesicles Isolated from the Brains of rTg4510 Mice Seed Tau Protein Aggregation in a Threshold-dependent Manner , 2016, The Journal of Biological Chemistry.

[3]  T. Ohm,et al.  Coupling of Mammalian Target of Rapamycin with Phosphoinositide 3-Kinase Signaling Pathway Regulates Protein Phosphatase 2A- and Glycogen Synthase Kinase-3β-dependent Phosphorylation of Tau* , 2008, Journal of Biological Chemistry.

[4]  M. Goedert,et al.  Like prions: the propagation of aggregated tau and &agr;-synuclein in neurodegeneration , 2017, Brain : a journal of neurology.

[5]  Hyun-Jeong Cho,et al.  DYRK1A-mediated Hyperphosphorylation of Tau , 2007, Journal of Biological Chemistry.

[6]  I. Ferrer,et al.  Tau‐positive nuclear indentations in P301S tauopathy mice , 2017, Brain pathology.

[7]  N. Hirokawa,et al.  Projection domains of MAP2 and tau determine spacings between microtubules in dendrites and axons , 1992, Nature.

[8]  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.

[9]  A J Lees,et al.  Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration , 2005, Journal of Medical Genetics.

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

[11]  M. Polymeropoulos,et al.  Abundant neuritic inclusions and microvacuolar changes in a case of diffuse Lewy body disease with the A53T mutation in the α-synuclein gene , 2005, Acta Neuropathologica.

[12]  B. Hyman,et al.  Are Tangles as Toxic as They Look? , 2011, Journal of Molecular Neuroscience.

[13]  Khadija Iqbal,et al.  Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. , 1998, Archives of biochemistry and biophysics.

[14]  E. Mandelkow,et al.  Aβ Oligomers Cause Localized Ca2+ Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines , 2010, The Journal of Neuroscience.

[15]  C. Yuan,et al.  Intrinsic Tau Acetylation Is Coupled to Auto-Proteolytic Tau Fragmentation , 2016, PloS one.

[16]  M. Vitek,et al.  Function of tau protein in adult newborn neurons , 2009, FEBS letters.

[17]  G. Drewes,et al.  The frontotemporal dementia mutation R406W blocks tau’s interaction with the membrane in an annexin A2–dependent manner , 2011, The Journal of cell biology.

[18]  B. Hyman,et al.  Nigral and Cortical Lewy Bodies and Dystrophic Nigral Neurites in Parkinson's Disease and Cortical Lewy Body Disease Contain α-synuclein Immunoreactivity , 1998, Journal of neuropathology and experimental neurology.

[19]  M. Ciotti,et al.  Identification of a caspase-derived N-terminal tau fragment in cellular and animal Alzheimer's disease models , 2008, Molecular and Cellular Neuroscience.

[20]  C. Geula,et al.  Selective tau tyrosine nitration in non-AD tauopathies , 2011, Acta Neuropathologica.

[21]  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.

[22]  S. Fujita,et al.  Inhibition of Protein Phosphatase 2A Overrides Tau Protein Kinase I/Glycogen Synthase Kinase 3β and Cyclin-dependent Kinase 5 Inhibition and Results in Tau Hyperphosphorylation in the Hippocampus of Starved Mouse* , 2001, The Journal of Biological Chemistry.

[23]  Kazuyuki Takata,et al.  Cdk5 Is a Key Factor in Tau Aggregation and Tangle Formation In Vivo , 2003, Neuron.

[24]  E. Mandelkow,et al.  Tau missorting and spastin-induced microtubule disruption in neurodegeneration: Alzheimer Disease and Hereditary Spastic Paraplegia , 2015, Molecular Neurodegeneration.

[25]  K. Ye,et al.  Asparagine endopeptidase is an innovative therapeutic target for neurodegenerative diseases , 2016, Expert opinion on therapeutic targets.

[26]  P. Mcgeer,et al.  Thrombin accumulation in brains of patients with Alzheimer's disease , 1992, Neuroscience Letters.

[27]  Jennifer Luebke,et al.  Depletion of microglia and inhibition of exosome synthesis halt tau propagation , 2015, Nature Neuroscience.

[28]  Ana Martins,et al.  A Powerful Yeast Model to Investigate the Synergistic Interaction of α-Synuclein and Tau in Neurodegeneration , 2013, PloS one.

[29]  A. Goldberg,et al.  Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling , 2015, Nature Medicine.

[30]  G. Werstuck,et al.  Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3 , 2005, Journal of Cell Science.

[31]  R. Malenka,et al.  A critical role for the PAR-1/MARK-tau axis in mediating the toxic effects of Aβ on synapses and dendritic spines. , 2012, Human molecular genetics.

[32]  H. Akiyama,et al.  Glial Tau Pathology in Neurodegenerative Diseases: Their Nature and Comparison with Neuronal Tangles , 1998, Neurobiology of Aging.

[33]  A. Andreadis,et al.  Pathogenic Forms of Tau Inhibit Kinesin-Dependent Axonal Transport through a Mechanism Involving Activation of Axonal Phosphotransferases , 2011, The Journal of Neuroscience.

[34]  Neurosci Lett , 2019 .

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

[36]  Christian Griesinger,et al.  The “Jaws” of the Tau-Microtubule Interaction* , 2007, Journal of Biological Chemistry.

[37]  R. Nixon,et al.  The role of autophagy in neurodegenerative disease , 2013, Nature Medicine.

[38]  Y. Ihara,et al.  Molecular aging of tau: disulfide‐independent aggregation and non‐enzymatic degradation in vitro and in vivo , 2004, Journal of neurochemistry.

[39]  J. Woodgett,et al.  The active form of glycogen synthase kinase-3β is associated with granulovacuolar degeneration in neurons in Alzheimer's disease , 2002, Acta Neuropathologica.

[40]  T. Shea Phospholipids alter tau conformation, phosphorylation, proteolysis, and association with microtubules: Implication for tau function under normal and degenerative conditions , 1997, Journal of neuroscience research.

[41]  E. Mandelkow,et al.  The natively unfolded character of tau and its aggregation to Alzheimer-like paired helical filaments. , 2008, Biochemistry.

[42]  C. López-Otín,et al.  Tau-related protein present in paired helical filaments has a decreased tubulin binding capacity as compared with microtubule-associated protein tau. , 1991, Biochimica et biophysica acta.

[43]  Qian-Qian Jiang,et al.  Region-specific expression of tau, amyloid-β protein precursor, and synaptic proteins at physiological condition or under endoplasmic reticulum stress in rats. , 2014, Journal of Alzheimer's disease : JAD.

[44]  Val Lowe,et al.  Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology. , 2013, Brain : a journal of neurology.

[45]  F. Foufelle,et al.  New insights into ER stress-induced insulin resistance , 2012, Trends in Endocrinology & Metabolism.

[46]  Shoji Komai,et al.  Characterization of Fyn-mediated Tyrosine Phosphorylation Sites on GluRε2 (NR2B) Subunit of theN-Methyl-d-aspartate Receptor* , 2001, The Journal of Biological Chemistry.

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

[48]  E. Mandelkow,et al.  Interaction of tau protein with model lipid membranes induces tau structural compaction and membrane disruption. , 2012, Biochemistry.

[49]  A. Goldberg,et al.  cAMP-induced phosphorylation of 26S proteasomes on Rpn6/PSMD11 enhances their activity and the degradation of misfolded proteins , 2015, Proceedings of the National Academy of Sciences.

[50]  U. Landegren,et al.  Elevated MARK2-dependent phosphorylation of Tau in Alzheimer's disease. , 2013, Journal of Alzheimer's disease : JAD.

[51]  E. Mandelkow,et al.  Swimming against the Tide: Mobility of the Microtubule-Associated Protein Tau in Neurons , 2007, The Journal of Neuroscience.

[52]  J. Brion,et al.  Reduction of acetylated alpha-tubulin immunoreactivity in neurofibrillary tangle-bearing neurons in Alzheimer's disease. , 1996, Journal of neuropathology and experimental neurology.

[53]  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.

[54]  Wendy Noble,et al.  Tau phosphorylation affects its axonal transport and degradation , 2013, Neurobiology of Aging.

[55]  Stephen B. Dunnett,et al.  Characterization of Progressive Motor Deficits in Mice Transgenic for the Human Huntington’s Disease Mutation , 1999, The Journal of Neuroscience.

[56]  F. J. Sullivan,et al.  Molecular phenotyping of aging in single yeast cells using a novel microfluidic device , 2012, Aging cell.

[57]  Manjit,et al.  Neurology , 1912, NeuroImage.

[58]  E. Marra,et al.  A peptide containing residues 26-44 of tau protein impairs mitochondrial oxidative phosphorylation acting at the level of the adenine nucleotide translocator. , 2008, Biochimica et biophysica acta.

[59]  Qian-Qian Jiang,et al.  LiCl attenuates thapsigargin-induced tau hyperphosphorylation by inhibiting GSK-3β in vivo and in vitro. , 2010, Journal of Alzheimer's disease : JAD.

[60]  S. Hébert,et al.  Tau hyperphosphorylation and deregulation of calcineurin in mouse models of Huntington's disease. , 2015, Human molecular genetics.

[61]  W. Klunk,et al.  Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B , 2004, Annals of neurology.

[62]  H. Paudel,et al.  14-3-3ζ Is an Effector of Tau Protein Phosphorylation* , 2000, The Journal of Biological Chemistry.

[63]  R. Nixon,et al.  Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[64]  D. Rubinsztein,et al.  Rapamycin alleviates toxicity of different aggregate-prone proteins. , 2006, Human molecular genetics.

[65]  G. Glenner,et al.  Neuritic plaques and cerebrovascular amyloid in Alzheimer disease are antigenically related. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[66]  R. Ravid,et al.  DC11: a novel monoclonal antibody revealing Alzheimer's disease-specific tau epitope , 2003, Neuroreport.

[67]  A. Ittner,et al.  Tau-Targeted Immunization Impedes Progression of Neurofibrillary Histopathology in Aged P301L Tau Transgenic Mice , 2011, PloS one.

[68]  R. Jope,et al.  Central Role of Glycogen Synthase Kinase-3β in Endoplasmic Reticulum Stress-induced Caspase-3 Activation* , 2002, The Journal of Biological Chemistry.

[69]  M. Vitek,et al.  Tau deficiency leads to the upregulation of BAF‐57, a protein involved in neuron‐specific gene repression , 2010, FEBS letters.

[70]  C. Hetz,et al.  Disturbance of endoplasmic reticulum proteostasis in neurodegenerative diseases , 2014, Nature Reviews Neuroscience.

[71]  A. Ittner SITE-SPECIFIC PHOSPHORYLATION OF TAU INHIBITS AMYLOID-β TOXICITY IN ALZHEIMER’S MICE , 2016, Alzheimer's & Dementia.

[72]  C. Barbato,et al.  Tau Cleavage and Dephosphorylation in Cerebellar Granule Neurons Undergoing Apoptosis , 1998, The Journal of Neuroscience.

[73]  M. Pool,et al.  Phosphorylation-mimicking glutamate clusters in the proline-rich region are sufficient to simulate the functional deficiencies of hyperphosphorylated tau protein. , 2001 .

[74]  B. Hyman,et al.  Tangle-Bearing Neurons Survive Despite Disruption of Membrane Integrity in a Mouse Model of Tauopathy , 2009, Journal of neuropathology and experimental neurology.

[75]  E. Mandelkow,et al.  Proteolytic processing of tau. , 2010, Biochemical Society transactions.

[76]  M. Hayden,et al.  Inhibition of Calpain Cleavage of Huntingtin Reduces Toxicity , 2004, Journal of Biological Chemistry.

[77]  C. Oliveira,et al.  A novel DYRK1A (Dual specificity tyrosine phosphorylation‐regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro , 2015, Journal of neurochemistry.

[78]  M. Zvelebil,et al.  Phosphorylation Regulates Tau Interactions with Src Homology 3 Domains of Phosphatidylinositol 3-Kinase, Phospholipase Cγ1, Grb2, and Src Family Kinases* , 2008, Journal of Biological Chemistry.

[79]  M. Meraz-Ríos,et al.  Tau oligomers and aggregation in Alzheimer’s disease , 2010, Journal of neurochemistry.

[80]  Jun Wang,et al.  Paired Helical Filaments from Alzheimer Disease Brain Induce Intracellular Accumulation of Tau Protein in Aggresomes* , 2012, The Journal of Biological Chemistry.

[81]  Max L. Valenstein,et al.  Graded Control of Microtubule Severing by Tubulin Glutamylation , 2016, Cell.

[82]  L. Mucke,et al.  Reducing Endogenous Tau Ameliorates Amyloid ß-Induced Deficits in an Alzheimer's Disease Mouse Model , 2007, Science.

[83]  R. Brandt,et al.  Systemic and network functions of the microtubule-associated protein tau: Implications for tau-based therapies , 2017, Molecular and Cellular Neuroscience.

[84]  P. Højrup,et al.  α-Synuclein Binds to Tau and Stimulates the Protein Kinase A-catalyzed Tau Phosphorylation of Serine Residues 262 and 356* , 1999, The Journal of Biological Chemistry.

[85]  J. Clarimón,et al.  Tau Enhances α-Synuclein Aggregation and Toxicity in Cellular Models of Synucleinopathy , 2011, PloS one.

[86]  I. Mansuy,et al.  The memory gene KIBRA is a bidirectional regulator of synaptic and structural plasticity in the adult brain , 2016, Neurobiology of Learning and Memory.

[87]  M. Weiner,et al.  Genome-wide association study identifies MAPT locus influencing human plasma tau levels , 2017, Neurology.

[88]  S. Lorenzl,et al.  Increased α-synuclein aggregation following limited cleavage by certain matrix metalloproteinases , 2009, Experimental Neurology.

[89]  R. Nitsch,et al.  Formation of Neurofibrillary Tangles in P301L Tau Transgenic Mice Induced by Aβ42 Fibrils , 2001, Science.

[90]  D. Bennett,et al.  Early N-Terminal Changes and Caspase-6 Cleavage of Tau in Alzheimer's Disease , 2004, The Journal of Neuroscience.

[91]  M. Radeke,et al.  Functional interactions between the proline-rich and repeat regions of tau enhance microtubule binding and assembly. , 1997, Molecular biology of the cell.

[92]  F. García-Sierra,et al.  Accumulation of Aspartic Acid421- and Glutamic Acid391-Cleaved Tau in Neurofibrillary Tangles Correlates With Progression in Alzheimer Disease , 2008, Journal of neuropathology and experimental neurology.

[93]  A. Fagan,et al.  Fine Mapping of Genetic Variants in BIN1, CLU, CR1 and PICALM for Association with Cerebrospinal Fluid Biomarkers for Alzheimer's Disease , 2011, PloS one.

[94]  T. Tabira,et al.  The twenty-four KDa C-terminal tau fragment increases with aging in tauopathy mice: implications of prion-like properties. , 2015, Human molecular genetics.

[95]  D. Dickson,et al.  Colocalization of Tau and Alpha‐Synuclein Epitopes in Lewy Bodies , 2003, Journal of neuropathology and experimental neurology.

[96]  D. Selkoe,et al.  Tau antisera recognize neurofibrillary tangles in a range of neurodegenerative disorders , 1987, Annals of neurology.

[97]  L. Blanchoin,et al.  Tau co-organizes dynamic microtubule and actin networks , 2015, Scientific Reports.

[98]  Andrew J. Payne,et al.  Caspase-3-Dependent Proteolytic Cleavage of Tau Causes Neurofibrillary Tangles and Results in Cognitive Impairment During Normal Aging , 2016, Neurochemical Research.

[99]  D. Dickson,et al.  An immunohistochemical study of cases of sporadic and inherited frontotemporal lobar degeneration using 3R- and 4R-specific tau monoclonal antibodies , 2006, Acta Neuropathologica.

[100]  M. Ciotti,et al.  Endogenous Aβ causes cell death via early tau hyperphosphorylation , 2011, Neurobiology of Aging.

[101]  E. Mandelkow,et al.  Linking Amyloid-β and Tau: Amyloid-β Induced Synaptic Dysfunction via Local Wreckage of the Neuronal Cytoskeleton , 2011, Neurodegenerative Diseases.

[102]  F. Polleux,et al.  The CAMKK2-AMPK Kinase Pathway Mediates the Synaptotoxic Effects of Aβ Oligomers through Tau Phosphorylation , 2013, Neuron.

[103]  L. Grinberg,et al.  Distinct Tau Prion Strains Propagate in Cells and Mice and Define Different Tauopathies , 2014, Neuron.

[104]  H. Akiyama,et al.  Different immunoreactivities of the microtubule-binding region of tau and its molecular basis in brains from patients with Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration , 2003, Acta Neuropathologica.

[105]  R. He,et al.  The proline-rich domain of tau plays a role in interactions with actin , 2009, BMC Cell Biology.

[106]  L. Buée,et al.  Ectosomes: A New Mechanism for Non-Exosomal Secretion of Tau Protein , 2014, PloS one.

[107]  S. Yen,et al.  Degradation of Tau by Lysosomal Enzyme Cathepsin D: Implication for Alzheimer Neurofibrillary Degeneration , 1997, Journal of neurochemistry.

[108]  E. Mandelkow,et al.  Autophagic degradation of tau in primary neurons and its enhancement by trehalose , 2012, Neurobiology of Aging.

[109]  J. Kuret,et al.  Casein kinase 1 delta is associated with pathological accumulation of tau in several neurodegenerative diseases , 2000, Neurobiology of Aging.

[110]  A. Roses,et al.  ApoE3 binding to tau tandem repeat I is abolished by tau serine262 phosphorylation , 1995, Neuroscience Letters.

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

[112]  S. Brady Mice overexpressing the human neurofilament heavy gene as a model of ALS , 1995, Neurobiology of Aging.

[113]  E. Bigio,et al.  Calpain-Mediated Tau Cleavage: A Mechanism Leading to Neurodegeneration Shared by Multiple Tauopathies , 2011, Molecular medicine.

[114]  J. Trojanowski,et al.  Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice , 2015, Neurobiology of Disease.

[115]  J. Trojanowski,et al.  The Microtubule-Stabilizing Agent, Epothilone D, Reduces Axonal Dysfunction, Neurotoxicity, Cognitive Deficits, and Alzheimer-Like Pathology in an Interventional Study with Aged Tau Transgenic Mice , 2012, The Journal of Neuroscience.

[116]  F. Tagliavini,et al.  A new function of microtubule-associated protein tau: Involvement in chromosome stability , 2008, Cell cycle.

[117]  G. Bloom Amyloid-β and tau: the trigger and bullet in Alzheimer disease pathogenesis. , 2014, JAMA neurology.

[118]  G. Schellenberg,et al.  Tau isoform regulation is region‐ and cell‐specific in mouse brain , 2008, The Journal of comparative neurology.

[119]  E. Mandelkow,et al.  Degradation of tau protein by autophagy and proteasomal pathways. , 2012, Biochemical Society transactions.

[120]  L. Buée,et al.  Loss of Tau protein affects the structure, transcription and repair of neuronal pericentromeric heterochromatin , 2016, Scientific Reports.

[121]  D. Constam,et al.  Cloning of the Human Puromycin‐Sensitive Aminopeptidase and Evidence for Expression in Neurons , 1997, Journal of neurochemistry.

[122]  H. Steinhoff,et al.  Global hairpin folding of tau in solution. , 2006, Biochemistry.

[123]  Stefani N. Thomas,et al.  Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity. , 2014, The Biochemical journal.

[124]  V. Lee,et al.  The microtubule-associated tau protein has intrinsic acetyltransferase activity , 2013, Nature Structural &Molecular Biology.

[125]  E. Mandelkow,et al.  Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. , 2009, Human molecular genetics.

[126]  J. Trojanowski,et al.  Tau-mediated neurodegeneration in Alzheimer's disease and related disorders , 2007, Nature Reviews Neuroscience.

[127]  L. Hersh,et al.  Studies on the Tissue Distribution of the Puromycin‐Sensitive Enkephalin‐Degrading Aminopeptidases , 1988, Journal of neurochemistry.

[128]  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.

[129]  M. Mattson,et al.  Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles Intracellular Aβ and Synaptic Dysfunction , 2003, Neuron.

[130]  I. Landrieu,et al.  Structural impact of heparin binding to full-length Tau as studied by NMR spectroscopy. , 2006, Biochemistry.

[131]  A. Andreadis Misregulation of tau alternative splicing in neurodegeneration and dementia. , 2006, Progress in molecular and subcellular biology.

[132]  David W. Colby,et al.  Conformational features of tau fibrils from Alzheimer's disease brain are faithfully propagated by unmodified recombinant protein. , 2013, Biochemistry.

[133]  W. Markesbery,et al.  Impaired Proteasome Function in Alzheimer's Disease , 2000, Journal of neurochemistry.

[134]  Ralph A. Nixon,et al.  Autophagy Induction and Autophagosome Clearance in Neurons: Relationship to Autophagic Pathology in Alzheimer's Disease , 2008, The Journal of Neuroscience.

[135]  W. Noble,et al.  Tyrosine phosphorylation of tau regulates its interactions with Fyn SH2 domains, but not SH3 domains, altering the cellular localization of tau , 2011, The FEBS journal.

[136]  J. Trojanowski,et al.  Epitopes that span the tau molecule are shared with paired helical filaments , 1988, Neuron.

[137]  K. Arima,et al.  NACP/α-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of parkinsonism and dementia with Lewy bodies: double-immunolabeling fluorescence and electron microscopic studies , 2000, Acta Neuropathologica.

[138]  E. Mandelkow,et al.  Tau protein and tau aggregation inhibitors , 2010, Neuropharmacology.

[139]  J. Trojanowski,et al.  Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains , 2015, Acta Neuropathologica.

[140]  David H. Cribbs,et al.  Aβ Immunotherapy Leads to Clearance of Early, but Not Late, Hyperphosphorylated Tau Aggregates via the Proteasome , 2004, Neuron.

[141]  Tim Scholz,et al.  Tau Protein Diffuses along the Microtubule Lattice* , 2012, The Journal of Biological Chemistry.

[142]  E. Seto,et al.  Lysine acetylation: codified crosstalk with other posttranslational modifications. , 2008, Molecular cell.

[143]  Li-Huei Tsai,et al.  Aberrant Cdk5 Activation by p25 Triggers Pathological Events Leading to Neurodegeneration and Neurofibrillary Tangles , 2003, Neuron.

[144]  C. Duyckaerts,et al.  The microtubule-associated protein tau is also phosphorylated on tyrosine. , 2009, Journal of Alzheimer's disease : JAD.

[145]  Frank M LaFerla,et al.  A novel BACE1-regulating protein with therapeutic potential , 2012, Alzheimer's & Dementia.

[146]  Mark Turmaine,et al.  Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation , 1997, Cell.

[147]  Ying Liu,et al.  Amyloid-like aggregates of neuronal tau induced by formaldehyde promote apoptosis of neuronal cells , 2007, BMC Neuroscience.

[148]  G. Schellenberg,et al.  A distinct familial presenile dementia with a novel missense mutation in the tau gene. , 1999, Neuroreport.

[149]  Richard Hollister,et al.  Neuronal loss correlates with but exceeds neurofibrillary tangles in Alzheimer's disease , 1997, Annals of neurology.

[150]  A. Lees,et al.  The Slow Axonal Transport of the Microtubule-Associated Protein Tau and the Transport Rates of Different Isoforms and Mutants in Cultured Neurons , 2002, The Journal of Neuroscience.

[151]  D. Hanger,et al.  Tau cleavage and tau aggregation in neurodegenerative disease. , 2010, Biochemical Society transactions.

[152]  S. Lipton,et al.  Synaptic Protein α1-Takusan Mitigates Amyloid-β-Induced Synaptic Loss via Interaction with Tau and Postsynaptic Density-95 at Postsynaptic Sites , 2013, The Journal of Neuroscience.

[153]  M. Navarrete,et al.  Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis , 2016, The EMBO journal.

[154]  E. Mandelkow,et al.  Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress , 2002, The Journal of cell biology.

[155]  R. Huber,et al.  HTRA proteases: regulated proteolysis in protein quality control , 2011, Nature Reviews Molecular Cell Biology.

[156]  J. Götz,et al.  Mobility and subcellular localization of endogenous, gene-edited Tau differs from that of over-expressed human wild-type and P301L mutant Tau , 2016, Scientific Reports.

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

[158]  D. Hanger,et al.  Functional implications of the association of tau with the plasma membrane. , 2010, Biochemical Society transactions.

[159]  D. Geschwind,et al.  A Genomic Screen for Modifiers of Tauopathy Identifies Puromycin-Sensitive Aminopeptidase as an Inhibitor of Tau-Induced Neurodegeneration , 2006, Neuron.

[160]  P. Cohen,et al.  Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B , 1995, Nature.

[161]  Naruhiko Sahara,et al.  Propagation of Tau Pathology in a Model of Early Alzheimer's Disease , 2012, Neuron.

[162]  Nigel J. Cairns,et al.  Filamentous α-synuclein inclusions link multiple system atrophy with Parkinson's disease and dementia with Lewy bodies , 1998, Neuroscience Letters.

[163]  Michel Goedert,et al.  Mutations causing neurodegenerative tauopathies. , 2005, Biochimica et biophysica acta.

[164]  H. Onoe,et al.  Differential regional distribution of phosphorylated tau and synapse loss in the nucleus accumbens in tauopathy model mice , 2011, Neurobiology of Disease.

[165]  Gloria Lee Tau and src family tyrosine kinases. , 2005, Biochimica et biophysica acta.

[166]  L. Christophorou Science , 2018, Emerging Dynamics: Science, Energy, Society and Values.

[167]  L. Buée,et al.  Prefibrillar Tau oligomers alter the nucleic acid protective function of Tau in hippocampal neurons in vivo , 2015, Neurobiology of Disease.

[168]  H. Wille,et al.  Conformational Diversity of Wild-type Tau Fibrils Specified by Templated Conformation Change* , 2009, Journal of Biological Chemistry.

[169]  J. Trojanowski,et al.  Acetylated tau neuropathology in sporadic and hereditary tauopathies. , 2013, The American journal of pathology.

[170]  B. Saccà,et al.  Determinants of amyloid fibril degradation by the PDZ protease HTRA1. , 2015, Nature chemical biology.

[171]  M. Baudry,et al.  Tyrosine phosphorylation of ionotropic glutamate receptors by Fyn or Src differentially modulates their susceptibility to calpain and enhances their binding to spectrin and PSD‐95 , 2001, Journal of neurochemistry.

[172]  Ruth Nussinov,et al.  Structural Insight into Tau Protein’s Paradox of Intrinsically Disordered Behavior, Self-Acetylation Activity, and Aggregation , 2014, The journal of physical chemistry letters.

[173]  B. Hyman,et al.  Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function , 2005, Science.

[174]  E. Mandelkow,et al.  Amyloid‐β oligomers induce synaptic damage via Tau‐dependent microtubule severing by TTLL6 and spastin , 2013, The EMBO journal.

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

[176]  M. Hemberg,et al.  Tau promotes neurodegeneration through global chromatin relaxation , 2014, Nature Neuroscience.

[177]  E. Mandelkow,et al.  Tau in physiology and pathology , 2015, Nature Reviews Neuroscience.

[178]  Tsuyoshi Morita,et al.  Specification of Neuronal Polarity Regulated by Local Translation of CRMP2 and Tau via the mTOR-p70S6K Pathway* , 2009, The Journal of Biological Chemistry.

[179]  George Perry,et al.  Activation of p38 Kinase Links Tau Phosphorylation, Oxidative Stress, and Cell Cycle‐Related Events in Alzheimer Disease , 2000 .

[180]  C. Jack,et al.  Clinicopathologic assessment and imaging of tauopathies in neurodegenerative dementias , 2014, Alzheimer's Research & Therapy.

[181]  P. Waters Fragile Y Chromosomes (retrospective on DOI 10.1002/bies.201500040) , 2017, BioEssays : news and reviews in molecular, cellular and developmental biology.

[182]  H. Braak,et al.  Alzheimer’s pathogenesis: is there neuron-to-neuron propagation? , 2011, Acta Neuropathologica.

[183]  S. Counts,et al.  Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport , 2016, Experimental Neurology.

[184]  K. Kosik,et al.  Competition for microtubule-binding with dual expression of tau missense and splice isoforms. , 2001, Molecular biology of the cell.

[185]  J. Bamburg,et al.  Neurodegenerative stimuli induce persistent ADF/cofilin–actin rods that disrupt distal neurite function , 2000, Nature Cell Biology.

[186]  Min Jae Lee,et al.  Tau degradation: The ubiquitin–proteasome system versus the autophagy-lysosome system , 2013, Progress in Neurobiology.

[187]  J. Lancia,et al.  Tau oligomers and tau toxicity in neurodegenerative disease. , 2012, Biochemical Society transactions.

[188]  C. Troakes,et al.  Prostate-derived Sterile 20-like Kinases (PSKs/TAOKs) Phosphorylate Tau Protein and Are Activated in Tangle-bearing Neurons in Alzheimer Disease* , 2013, The Journal of Biological Chemistry.

[189]  R. Llinás,et al.  Tau pathology-mediated presynaptic dysfunction , 2016, Neuroscience.

[190]  L. Behar,et al.  Axonal Tau mRNA Localization Coincides with Tau Protein in Living Neuronal Cells and Depends on Axonal Targeting Signal , 2001, The Journal of Neuroscience.

[191]  A. Buisson,et al.  Activity-Dependent Tau Protein Translocation to Excitatory Synapse Is Disrupted by Exposure to Amyloid-Beta Oligomers , 2014, The Journal of Neuroscience.

[192]  G M Cohen,et al.  Caspases: the executioners of apoptosis. , 1997, The Biochemical journal.

[193]  John Hardy,et al.  CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation , 2004 .

[194]  E. Mandelkow,et al.  Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[195]  M. Ciotti,et al.  AD-linked, toxic NH2 human tau affects the quality control of mitochondria in neurons , 2014, Neurobiology of Disease.

[196]  D. Wilkin,et al.  Neuron , 2001, Brain Research.

[197]  F. Jin,et al.  Alzheimer’s disease and gut microbiota , 2016, Science China Life Sciences.

[198]  D. Hanger,et al.  Reduced number of axonal mitochondria and tau hypophosphorylation in mouse P301L tau knockin neurons , 2016, Neurobiology of Disease.

[199]  Christian Griesinger,et al.  Structural Polymorphism of 441-Residue Tau at Single Residue Resolution , 2009, PLoS biology.

[200]  J. Lucas,et al.  Faulty splicing and cytoskeleton abnormalities in Huntington's disease , 2016, Brain pathology.

[201]  R. Huber,et al.  Human High Temperature Requirement Serine Protease A1 (HTRA1) Degrades Tau Protein Aggregates* , 2012, The Journal of Biological Chemistry.

[202]  W. Scheper,et al.  Endoplasmic reticulum: the unfolded protein response is tangled in neurodegeneration. , 2012, The international journal of biochemistry & cell biology.

[203]  W. Noble,et al.  Molecular motors implicated in the axonal transport of tau and α-synuclein , 2005, Journal of Cell Science.

[204]  M. Mercken,et al.  Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[205]  J. Abisambra,et al.  Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation , 2013, Alzheimer's & Dementia.

[206]  N. Sousa,et al.  Absence of Tau triggers age‐dependent sciatic nerve morphofunctional deficits and motor impairment , 2016, Aging cell.

[207]  J. Ávila,et al.  τ Protein from Alzheimer's Disease Patients Is Glycated at Its Tubulin‐Binding Domain , 1995, Journal of neurochemistry.

[208]  P. Fraser Prions and Prion-like Proteins , 2014, The Journal of Biological Chemistry.

[209]  Khadija Iqbal,et al.  Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. , 2008, Current medicinal chemistry.

[210]  Kazuhiro Oiwa,et al.  Single‐molecule investigation of the interference between kinesin, tau and MAP2c , 2002, The EMBO journal.

[211]  Cam Patterson,et al.  The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. , 2007, The Journal of clinical investigation.

[212]  R. Wade-Martins Genetics: The MAPT locus—a genetic paradigm in disease susceptibility , 2012, Nature Reviews Neurology.

[213]  Keith A. Johnson,et al.  Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: a chameleon for neuropathology and neuroimaging , 2015, Neuropathology and applied neurobiology.

[214]  P. Dolan,et al.  The role of tau kinases in Alzheimer's disease. , 2010, Current opinion in drug discovery & development.

[215]  N. Zilka,et al.  Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway , 2011, The Journal of Immunology.

[216]  I. Grundke‐Iqbal,et al.  Site‐specific effects of tau phosphorylation on its microtubule assembly activity and self‐aggregation , 2007, The European journal of neuroscience.

[217]  Hu Li,et al.  Interaction of tau with the RNA-Binding Protein TIA1 Regulates tau Pathophysiology and Toxicity. , 2016, Cell reports.

[218]  Casey Cook,et al.  Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance , 2013, Human molecular genetics.

[219]  J. Trojanowski,et al.  Initiation and Synergistic Fibrillization of Tau and Alpha-Synuclein , 2003, Science.

[220]  P. Verstreken,et al.  Loss of Bin1 Promotes the Propagation of Tau Pathology. , 2016, Cell reports.

[221]  J. Ávila,et al.  Tau protein provides DNA with thermodynamic and structural features which are similar to those found in histone-DNA complex. , 2014, Journal of Alzheimer's disease : JAD.

[222]  Mathias Jucker,et al.  Self-propagation of pathogenic protein aggregates in neurodegenerative diseases , 2013, Nature.

[223]  R. Williams,et al.  Microtubule-associated proteins connect microtubules and neurofilaments in vitro. , 1984, Biochemistry.

[224]  J. Kordower,et al.  Substantia nigra tangles are related to gait impairment in older persons , 2006, Annals of neurology.

[225]  Wendy Noble,et al.  Physiological release of endogenous tau is stimulated by neuronal activity , 2013, EMBO reports.

[226]  S. Lovestone,et al.  Effects of FTDP‐17 mutations on the in vitro phosphorylation of tau by glycogen synthase kinase 3β identified by mass spectrometry demonstrate certain mutations exert long‐range conformational changes , 2001, FEBS letters.

[227]  R. Huganir,et al.  Tau phosphorylation and tau mislocalization mediate soluble Aβ oligomer‐induced AMPA glutamate receptor signaling deficits , 2014, The European journal of neuroscience.

[228]  Wen-Lang Lin,et al.  Autophagic‐lysosomal perturbation enhances tau aggregation in transfectants with induced wild‐type tau expression , 2008, The European journal of neuroscience.

[229]  Q. Tian,et al.  Bip enhanced the association of GSK-3β with tau during ER stress both in vivo and in vitro. , 2012, Journal of Alzheimer's disease : JAD.

[230]  K. Zahs,et al.  Caspase-2 cleavage of tau reversibly impairs memory , 2016, Nature Medicine.

[231]  I. Landrieu,et al.  NMR investigation of the interaction between the neuronal protein tau and the microtubules. , 2007, Biochemistry.

[232]  W. Scheper,et al.  Unfolded protein response activates glycogen synthase kinase-3 via selective lysosomal degradation , 2013, Neurobiology of Aging.

[233]  S. Hubbard,et al.  How IRE1 Reacts to ER Stress , 2008, Cell.

[234]  Akihiko Takashima,et al.  Chaperones increase association of tau protein with microtubules , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[235]  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.

[236]  E. Mandelkow,et al.  Biochemistry and cell biology of tau protein in neurofibrillary degeneration. , 2012, Cold Spring Harbor perspectives in medicine.

[237]  A. Ittner,et al.  Tau‐targeted treatment strategies in Alzheimer's disease , 2012, British journal of pharmacology.

[238]  R. Berry,et al.  Inhibition of tau polymerization by its carboxy-terminal caspase cleavage fragment. , 2003, Biochemistry.

[239]  A. McKee,et al.  Exosome-associated Tau Is Secreted in Tauopathy Models and Is Selectively Phosphorylated in Cerebrospinal Fluid in Early Alzheimer Disease* , 2011, The Journal of Biological Chemistry.

[240]  James L. Buescher,et al.  Tau‐tubulin kinase 1 (TTBK1), a neuron‐specific tau kinase candidate, is involved in tau phosphorylation and aggregation , 2006, Journal of neurochemistry.

[241]  S. Albrecht,et al.  Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease. , 2004, The American journal of pathology.

[242]  T. Hortobágyi,et al.  Evidence that the presynaptic vesicle protein CSPalpha is a key player in synaptic degeneration and protection in Alzheimer’s disease , 2015, Molecular Brain.

[243]  W. Noble,et al.  Dynamic association of tau with neuronal membranes is regulated by phosphorylation , 2012, Neurobiology of Aging.

[244]  S. Prusiner Novel proteinaceous infectious particles cause scrapie. , 1982, Science.

[245]  A. Lees,et al.  The complex relationship between soluble and insoluble tau in tauopathies revealed by efficient dephosphorylation and specific antibodies , 2002, FEBS letters.

[246]  J. Wu,et al.  Specific processing of native and phosphorylated tau protein by proteases. , 1996, Biochemical and biophysical research communications.

[247]  Meaghan Morris,et al.  The Many Faces of Tau , 2011, Neuron.

[248]  Steven P. Gygi,et al.  CHIP-Hsc70 Complex Ubiquitinates Phosphorylated Tau and Enhances Cell Survival* , 2004, Journal of Biological Chemistry.

[249]  D. Rubinsztein,et al.  The roles of intracellular protein-degradation pathways in neurodegeneration , 2006, Nature.

[250]  C. Chirita,et al.  Pathways of tau fibrillization. , 2005, Biochimica et biophysica acta.

[251]  K. Tamura,et al.  Stimulatory effect of α‐synuclein on the tau‐phosphorylation by GSK‐3β , 2011, The FEBS journal.

[252]  W. Scheper,et al.  The unfolded protein response in neurodegenerative diseases: a neuropathological perspective , 2015, Acta Neuropathologica.

[253]  E. Masliah,et al.  Mechanisms of synaptic dysfunction in Alzheimer's disease. , 1995, Histology and histopathology.

[254]  M. Colin,et al.  Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies , 2016, Acta neuropathologica communications.

[255]  Qian Sun,et al.  Tau phosphorylation by GSK-3β promotes tangle-like filament morphology , 2007, Molecular Neurodegeneration.

[256]  P. Filipcik,et al.  Truncated tau expression levels determine life span of a rat model of tauopathy without causing neuronal loss or correlating with terminal neurofibrillary tangle load , 2008, The European journal of neuroscience.

[257]  M. Xue,et al.  The Ambiguous Relationship of Oxidative Stress, Tau Hyperphosphorylation, and Autophagy Dysfunction in Alzheimer's Disease , 2015, Oxidative medicine and cellular longevity.

[258]  N. Leclerc,et al.  Tau Accumulation, Altered Phosphorylation, and Missorting Promote Neurodegeneration in Glaucoma , 2016, The Journal of Neuroscience.

[259]  L. Raymond,et al.  Cleavage at the Caspase-6 Site Is Required for Neuronal Dysfunction and Degeneration Due to Mutant Huntingtin , 2006, Cell.

[260]  R. Berry,et al.  Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: in vitro evidence and implications for tangle formation in vivo , 2006, Journal of neurochemistry.

[261]  Alfonso Baldi,et al.  Implications of the serine protease HtrA1 in amyloid precursor protein processing , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[262]  Xiaohong Zhou,et al.  The proline-rich domain and the microtubule binding domain of protein tau acting as RNA binding domains. , 2006, Protein and peptide letters.

[263]  C. Cotman,et al.  Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. , 2004, The Journal of clinical investigation.

[264]  J. Trojanowski,et al.  Expression of TDP-43 C-terminal Fragments in Vitro Recapitulates Pathological Features of TDP-43 Proteinopathies* , 2009, Journal of Biological Chemistry.

[265]  M. Novák Truncated tau protein as a new marker for Alzheimer's disease. , 1994, Acta virologica.

[266]  H. Vinters,et al.  Pre‐synaptic C‐terminal truncated tau is released from cortical synapses in Alzheimer's disease , 2015, Journal of neurochemistry.

[267]  G. Perry,et al.  Selenoprotein S Reduces Endoplasmic Reticulum Stress-Induced Phosphorylation of Tau: Potential Role in Selenate Mitigation of Tau Pathology. , 2016, Journal of Alzheimer's disease : JAD.

[268]  E. Bird,et al.  Lysosomal proteinase antigens are prominently localized within senile plaques of Alzheimer's disease: evidence for a neuronal origin , 1990, Brain Research.

[269]  T. Arendt,et al.  Tau and tauopathies , 2016, Brain Research Bulletin.

[270]  V. Haroutunian,et al.  Acetylation of Tau Inhibits Its Degradation and Contributes to Tauopathy , 2010, Neuron.

[271]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[272]  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.

[273]  E. Roberson,et al.  The dendritic hypothesis for Alzheimer's disease pathophysiology , 2014, Brain Research Bulletin.

[274]  I. Correas,et al.  The tubulin-binding sequence of brain microtubule-associated proteins, tau and MAP-2, is also involved in actin binding. , 1990, The Biochemical journal.

[275]  Ayodeji A. Asuni,et al.  Immunotherapy Targeting Pathological Tau Conformers in a Tangle Mouse Model Reduces Brain Pathology with Associated Functional Improvements , 2007, The Journal of Neuroscience.

[276]  M. Sudol,et al.  The importance of being proline: the interaction of proline‐rich motifs in signaling proteins with their cognate domains , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[277]  G. Lynch,et al.  Cytosolic Proteolysis of τ by Cathepsin D in Hippocampus Following Suppression of Cathepsins B and L , 1996, Journal of neurochemistry.

[278]  I. Ferrer,et al.  Huntington's disease is a four-repeat tauopathy with tau nuclear rods , 2014, Nature Medicine.

[279]  P. Reddy,et al.  Impaired mitochondrial dynamics and abnormal interaction of amyloid beta with mitochondrial protein Drp1 in neurons from patients with Alzheimer's disease: implications for neuronal damage. , 2011, Human molecular genetics.

[280]  F. Tagliavini,et al.  Mutations in MAPT gene cause chromosome instability and introduce copy number variations widely in the genome. , 2013, Journal of Alzheimer's disease : JAD.

[281]  J. Trojanowski,et al.  Parkinson's disease dementia: convergence of α-synuclein, tau and amyloid-β pathologies , 2013, Nature Reviews Neuroscience.

[282]  C. Cotman,et al.  Caspase-9 Activation and Caspase Cleavage of tau in the Alzheimer's Disease Brain , 2002, Neurobiology of Disease.

[283]  Irving E. Vega,et al.  Increase in tau tyrosine phosphorylation correlates with the formation of tau aggregates. , 2005, Brain research. Molecular brain research.

[284]  J. Miklossy,et al.  Thrombin and Prothrombin Are Expressed by Neurons and Glial Cells and Accumulate in Neurofibrillary Tangles in Alzheimer Disease Brain , 2006, Journal of neuropathology and experimental neurology.

[285]  D. Xia,et al.  Pseudophosphorylation of Tau at distinct epitopes or the presence of the P301L mutation targets the microtubule-associated protein Tau to dendritic spines. , 2015, Biochimica et biophysica acta.

[286]  E. Mandelkow,et al.  Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model , 2007, Proceedings of the National Academy of Sciences.

[287]  P. Baas,et al.  Microtubules in health and degenerative disease of the nervous system , 2016, Brain Research Bulletin.

[288]  C. Zurzolo,et al.  Small Misfolded Tau Species Are Internalized via Bulk Endocytosis and Anterogradely and Retrogradely Transported in Neurons* , 2012, The Journal of Biological Chemistry.

[289]  Jürgen Götz,et al.  Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models , 2010, Cell.

[290]  Nancy Ratner,et al.  Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin‐based motility , 2002, The EMBO journal.

[291]  Sangmook Lee,et al.  Interneuronal transfer of human tau between Lamprey central neurons in situ. , 2010, Journal of Alzheimer's disease : JAD.

[292]  E. Huang,et al.  Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation , 2013, Acta Neuropathologica.

[293]  M. Farrer,et al.  MAPT H1 haplotype is a risk factor for essential tremor and multiple system atrophy , 2011, Neurology.

[294]  J. Götz,et al.  Phosphorylated Tau Interacts with c-Jun N-terminal Kinase-interacting Protein 1 (JIP1) in Alzheimer Disease* , 2009, The Journal of Biological Chemistry.

[295]  G. Drewes,et al.  Tau interactome mapping based identification of Otub1 as Tau deubiquitinase involved in accumulation of pathological Tau forms in vitro and in vivo , 2017, Acta Neuropathologica.

[296]  I. Grundke‐Iqbal,et al.  Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration , 2007, The European journal of neuroscience.

[297]  L. Buée,et al.  Nuclear magnetic resonance spectroscopy characterization of interaction of Tau with DNA and its regulation by phosphorylation. , 2015, Biochemistry.

[298]  F. Brodsky,et al.  Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds , 2013, Proceedings of the National Academy of Sciences.

[299]  Jian-Zhi Wang,et al.  SIL1 Rescued Bip Elevation-Related Tau Hyperphosphorylation in ER Stress , 2015, Molecular Neurobiology.

[300]  Menno P. Witter,et al.  Trans-Synaptic Spread of Tau Pathology In Vivo , 2012, PloS one.

[301]  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.

[302]  W. Poon,et al.  Caspase-Cleaved Tau Co-Localizes with Early Tangle Markers in the Human Vascular Dementia Brain , 2015, PloS one.

[303]  R. Nitsch,et al.  Proteasome inhibition by paired helical filament‐tau in brains of patients with Alzheimer's disease , 2003, Journal of neurochemistry.

[304]  Xiongwei Zhu,et al.  Phosphorylation of Tau Protein as the Link between Oxidative Stress, Mitochondrial Dysfunction, and Connectivity Failure: Implications for Alzheimer's Disease , 2013, Oxidative medicine and cellular longevity.

[305]  T. Hortobágyi,et al.  Tauopathy induced by low level expression of a human brain-derived tau fragment in mice is rescued by phenylbutyrate , 2016, Brain : a journal of neurology.

[306]  J. Trojanowski,et al.  The acetylation of tau inhibits its function and promotes pathological tau aggregation. , 2011, Nature communications.

[307]  G. Pasinetti,et al.  Akt/PKB kinase phosphorylates separately Thr212 and Ser214 of tau protein in vitro. , 2003, Biochimica et biophysica acta.

[308]  Peter Tompa,et al.  On the Sequential Determinants of Calpain Cleavage* , 2004, Journal of Biological Chemistry.

[309]  G. Johnson,et al.  Localization and in situ phosphorylation state of nuclear tau. , 1995, Experimental cell research.

[310]  O. Levy,et al.  The neuropathology of genetic Parkinson's disease , 2012, Movement disorders : official journal of the Movement Disorder Society.

[311]  W. Scheper,et al.  The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies , 2012, The Journal of pathology.

[312]  A. Anderson,et al.  Morphological and biochemical assessment of DNA damage and apoptosis in Down syndrome and Alzheimer disease, and effect of postmortem tissue archival on TUNEL , 2000, Neurobiology of Aging.

[313]  R. Zinkowski,et al.  Presence of tau in isolated nuclei from human brain , 1995, Neurobiology of Aging.

[314]  Dennis W. Dickson,et al.  Neuropathology of Frontotemporal Lobar Degeneration-Tau (FTLD-Tau) , 2011, Journal of Molecular Neuroscience.

[315]  R. Huganir,et al.  Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss , 2016, Neuron.

[316]  C. Richter-Landsberg,et al.  Expression of microtubule-associated proteins MAP2 and tau in cultured rat brain oligodendrocytes , 1997, Cell and Tissue Research.

[317]  A. Klug,et al.  Structural characterization of the core of the paired helical filament of Alzheimer disease. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[318]  P. Cohen,et al.  Molecular dissection of the paired helical filament , 1995, Neurobiology of Aging.

[319]  Lynn A. Hyde,et al.  Analysis of tau post-translational modifications in rTg4510 mice, a model of tau pathology , 2015, Molecular Neurodegeneration.

[320]  P. Szekeres,et al.  Short Fibrils Constitute the Major Species of Seed-Competent Tau in the Brains of Mice Transgenic for Human P301S Tau , 2016, The Journal of Neuroscience.

[321]  T. Wollert Autophagy , 2019, Current Biology.

[322]  A. Prokop,et al.  Tau and spectraplakins promote synapse formation and maintenance through Jun kinase and neuronal trafficking , 2016, eLife.

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

[324]  G. Schmitt-Ulms,et al.  The Human Tau Interactome: Binding to the Ribonucleoproteome, and Impaired Binding of the Proline-to-Leucine Mutant at Position 301 (P301L) to Chaperones and the Proteasome* , 2015, Molecular & Cellular Proteomics.

[325]  K. Ashe,et al.  Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration , 2010, Neuron.

[326]  Luc Bracoud,et al.  Efficacy and safety of tau-aggregation inhibitor therapy in patients with mild or moderate Alzheimer's disease: a randomised, controlled, double-blind, parallel-arm, phase 3 trial , 2016, The Lancet.

[327]  A. Giese,et al.  Synergistic influence of phosphorylation and metal ions on tau oligomer formation and coaggregation with α-synuclein at the single molecule level , 2012, Molecular Neurodegeneration.

[328]  Siamak Shahidi,et al.  BRAIN RES BULL , 2008 .

[329]  M. Diamond,et al.  Propagation of Tau Misfolding from the Outside to the Inside of a Cell* , 2009, Journal of Biological Chemistry.

[330]  N. Hirokawa,et al.  Gem GTPase and Tau , 2004, Journal of Biological Chemistry.

[331]  G. Sancesario,et al.  A NH2 tau fragment targets neuronal mitochondria at AD synapses: possible implications for neurodegeneration. , 2010, Journal of Alzheimer's disease : JAD.

[332]  P. Davies,et al.  A preparation of Alzheimer paired helical filaments that displays distinct tau proteins by polyacrylamide gel electrophoresis. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[333]  V. Hu The Cell Cycle , 1994, GWUMC Department of Biochemistry Annual Spring Symposia.

[334]  J. Lambert,et al.  Tau phosphorylation regulates the interaction between BIN1’s SH3 domain and Tau’s proline-rich domain , 2015, Acta Neuropathologica Communications.

[335]  R. Chang,et al.  Endoplasmic reticulum stress induces tau pathology and forms a vicious cycle: implication in Alzheimer's disease pathogenesis. , 2012, Journal of Alzheimer's disease : JAD.

[336]  H. Vinters,et al.  Loss of O-GlcNAc glycosylation in forebrain excitatory neurons induces neurodegeneration , 2016, Proceedings of the National Academy of Sciences.

[337]  Burton S. Rosner,et al.  Neuropharmacology , 1958, Nature.

[338]  K. Scearce-Levie,et al.  Antibody-Mediated Targeting of Tau In Vivo Does Not Require Effector Function and Microglial Engagement. , 2016, Cell reports.

[339]  J. Götz,et al.  Profiling Murine Tau with 0N, 1N and 2N Isoform-Specific Antibodies in Brain and Peripheral Organs Reveals Distinct Subcellular Localization, with the 1N Isoform Being Enriched in the Nucleus , 2013, PloS one.

[340]  L. Buée,et al.  Nuclear Tau, a Key Player in Neuronal DNA Protection* , 2010, The Journal of Biological Chemistry.

[341]  A. Delacourte,et al.  Tau protein as a differential biomarker of tauopathies. , 2005, Biochimica et biophysica acta.

[342]  P. Davies,et al.  Determination of peptide substrate specificity for mu-calpain by a peptide library-based approach: the importance of primed side interactions. , 2005, The Journal of biological chemistry.

[343]  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.

[344]  F. Wouters,et al.  α-Synuclein and its disease-related mutants interact differentially with the microtubule protein tau and associate with the actin cytoskeleton , 2007, Neurobiology of Disease.

[345]  E. Mandelkow,et al.  Proline-directed Pseudo-phosphorylation at AT8 and PHF1 Epitopes Induces a Compaction of the Paperclip Folding of Tau and Generates a Pathological (MC-1) Conformation* , 2008, Journal of Biological Chemistry.

[346]  P. Dolan,et al.  Caspase-cleaved Tau Expression Induces Mitochondrial Dysfunction in Immortalized Cortical Neurons , 2009, The Journal of Biological Chemistry.

[347]  S. Younkin,et al.  Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice , 1996, Science.

[348]  G. Johnson,et al.  Phosphorylation by cAMP-dependent protein kinase inhibits the degradation of tau by calpain. , 1992, The Journal of biological chemistry.

[349]  F. Dahlquist,et al.  A soluble oligomer of tau associated with fiber formation analyzed by NMR. , 2008, Biochemistry.

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

[351]  Elisabeth L. Moussaud-Lamodière,et al.  Alpha-synuclein and tau: teammates in neurodegeneration? , 2014, Molecular Neurodegeneration.

[352]  K. Kosaka,et al.  Occurrence of human α-synuclein immunoreactive neurons with neurofibrillary tangle formation in the limbic areas of patients with Alzheimer’s disease , 2000, Journal of the Neurological Sciences.

[353]  M. Hasegawa,et al.  The Relationship Between Development of Neuronal and Astrocytic Tau Pathologies in Subcortical Nuclei and Progression of Argyrophilic Grain Disease , 2016, Brain pathology.

[354]  M. Feany,et al.  Lysosomal Dysfunction Promotes Cleavage and Neurotoxicity of Tau In Vivo , 2010, PLoS genetics.

[355]  R. Morimoto,et al.  Huntington's disease: underlying molecular mechanisms and emerging concepts. , 2013, Trends in biochemical sciences.

[356]  Chuong B. Do,et al.  Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease , 2014, Nature Genetics.

[357]  R. Hamilton,et al.  Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease , 2009, Proceedings of the National Academy of Sciences.

[358]  L. Binder,et al.  Phosphorylation determines two distinct species of Tau in the central nervous system. , 1987, Cell motility and the cytoskeleton.

[359]  R. Berry,et al.  Caspase cleavage of tau: Linking amyloid and neurofibrillary tangles in Alzheimer's disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[360]  L. Buée,et al.  Lithium treatment arrests the development of neurofibrillary tangles in mutant tau transgenic mice with advanced neurofibrillary pathology. , 2010, Journal of Alzheimer's disease : JAD.

[361]  A. Lang,et al.  Interface between tauopathies and synucleinopathies: A tale of two proteins , 2006, Annals of neurology.

[362]  A M Gronenborn,et al.  Minor groove-binding architectural proteins: structure, function, and DNA recognition. , 1998, Annual review of biophysics and biomolecular structure.

[363]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[364]  T. Südhof,et al.  CSPα knockout causes neurodegeneration by impairing SNAP‐25 function , 2012, The EMBO journal.

[365]  P. Janmey,et al.  The structure of divalent cation-induced aggregates of PIP2 and their alteration by gelsolin and tau. , 1997, Biophysical journal.

[366]  P. Dolan,et al.  Histone deacetylase 6 interacts with the microtubule‐associated protein tau , 2008, Journal of neurochemistry.

[367]  Meaghan Morris,et al.  Tau post-translational modifications in wildtype and human amyloid precursor protein transgenic mice , 2015, Nature Neuroscience.

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

[369]  S. Gauthier,et al.  Paired helical filaments and the cytoplasmic-nuclear interface in Alzheimer's disease , 1988, Journal of neurocytology.

[370]  P. Baráth,et al.  N-terminal truncation of microtubule associated protein tau dysregulates its cellular localization. , 2014, Journal of Alzheimer's disease : JAD.

[371]  A. Lang,et al.  Neuronal degeneration, synaptic defects, and behavioral abnormalities in tau45-230 transgenic mice , 2014, Neuroscience.

[372]  H. Akiyama,et al.  Neurons containing Alz-50-immunoreactive granules around the cerebral infarction: evidence for the lysosomal degradation of altered tau in human brain? , 2000, Neuroscience Letters.

[373]  E. Klann,et al.  Macroautophagy deficiency mediates age-dependent neurodegeneration through a phospho-tau pathway , 2012, Molecular Neurodegeneration.

[374]  Y. Liu,et al.  Hyperphosphorylation results in tau dysfunction in DNA folding and protection. , 2013, Journal of Alzheimer's disease : JAD.

[375]  Simone Lista,et al.  Advances in the therapy of Alzheimer’s disease: targeting amyloid beta and tau and perspectives for the future , 2015, Expert review of neurotherapeutics.

[376]  J. Kabat,et al.  Molecular characterization of the minimal protease resistant tau unit of the Alzheimer's disease paired helical filament. , 1993, The EMBO journal.

[377]  Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways , 2012, Journal of Neuroinflammation.

[378]  M. Halliday,et al.  PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia , 2015, Acta Neuropathologica.

[379]  N. Leclerc,et al.  Interaction of Endogenous Tau Protein with Synaptic Proteins Is Regulated by N-Methyl-d-aspartate Receptor-dependent Tau Phosphorylation* , 2012, The Journal of Biological Chemistry.

[380]  U. Kang,et al.  Membrane Depolarization Induces the Undulating Phosphorylation/Dephosphorylation of Glycogen Synthase Kinase 3β, and This Dephosphorylation Involves Protein Phosphatases 2A and 2B in SH-SY5Y Human Neuroblastoma Cells* , 2005, Journal of Biological Chemistry.

[381]  L. Buée,et al.  A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions , 2014, Front. Cell. Neurosci..

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

[383]  J. M. Lee,et al.  Tau phosphorylation increases in symptomatic mice overexpressing A30P α-synuclein , 2005, Experimental Neurology.

[384]  T. Montine,et al.  Proteomic Identification of Novel Proteins in Cortical Lewy Bodies , 2007, Brain pathology.

[385]  A. Borreca,et al.  NH2-truncated human tau induces deregulated mitophagy in neurons by aberrant recruitment of Parkin and UCHL-1: implications in Alzheimer's disease. , 2015, Human molecular genetics.

[386]  M. Diamond,et al.  Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo , 2016, Neuron.

[387]  R. Barker,et al.  GSK-3β-induced Tau pathology drives hippocampal neuronal cell death in Huntington's disease: involvement of astrocyte–neuron interactions , 2016, Cell Death and Disease.

[388]  Jürgen Götz,et al.  Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia , 2008, Proceedings of the National Academy of Sciences.

[389]  Xiongwei Zhu,et al.  Tau – an inhibitor of deacetylase HDAC6 function , 2009, Journal of neurochemistry.

[390]  A. Mietelska-Porowska,et al.  Tau Protein Modifications and Interactions: Their Role in Function and Dysfunction , 2014, International journal of molecular sciences.

[391]  A. Grierson,et al.  Role of axonal transport in neurodegenerative diseases. , 2008, Annual review of neuroscience.

[392]  S. Yen,et al.  Tyrosine phosphorylation of tau accompanies disease progression in transgenic mouse models of tauopathy , 2010, Neuropathology and applied neurobiology.

[393]  廣瀬雄一,et al.  Neuroscience , 2019, Workplace Attachments.

[394]  G. Perry,et al.  Conformational changes and cleavage of tau in Pick bodies parallel the early processing of tau found in Alzheimer pathology , 2007, Neuropathology and applied neurobiology.

[395]  F. Young Biochemistry , 1955, The Indian Medical Gazette.

[396]  T. Zalewska,et al.  Is calpain activity regulated by membranes and autolysis or by calcium and calpastatin? , 1992, BioEssays : news and reviews in molecular, cellular and developmental biology.

[397]  L. Binder,et al.  Identification of nuclear tau isoforms in human neuroblastoma cells. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[398]  R. D'Hooge,et al.  Cognition and hippocampal synaptic plasticity in mice with a homozygous tau deletion , 2014, Neurobiology of Aging.

[399]  B. Liu,et al.  Glycogen synthase kinase-3β regulates Tyr307 phosphorylation of protein phosphatase-2A via protein tyrosine phosphatase 1B but not Src. , 2011, The Biochemical journal.

[400]  A. Sidhu,et al.  Tauopathic Changes in the Striatum of A53T α-Synuclein Mutant Mouse Model of Parkinson's Disease , 2011, PloS one.

[401]  Youssra K Al-Hilaly,et al.  Nuclear Tau and Its Potential Role in Alzheimer’s Disease , 2016, Biomolecules.

[402]  P. Filipcik,et al.  Expression of a truncated tau protein induces oxidative stress in a rodent model of tauopathy , 2006, The European journal of neuroscience.

[403]  E. Bigio,et al.  Phosphorylation and cleavage of tau in non-AD tauopathies , 2007, Acta Neuropathologica.

[404]  D. Selkoe,et al.  Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration , 2011, Proceedings of the National Academy of Sciences.

[405]  A. Morton,et al.  Selective Discrimination Learning Impairments in Mice Expressing the Human Huntington's Disease Mutation , 1999, The Journal of Neuroscience.

[406]  C. Koumenis,et al.  The PERK/eIF2α/ATF4 module of the UPR in hypoxia resistance and tumor growth , 2006 .

[407]  Alcino J. Silva,et al.  mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies , 2013, Aging cell.

[408]  G. Perry,et al.  Neurotoxic dopamine quinone facilitates the assembly of tau into fibrillar polymers , 2005, Molecular and Cellular Biochemistry.

[409]  P. Mcgeer,et al.  Proteolysis of Non-phosphorylated and Phosphorylated Tau by Thrombin* , 2005, Journal of Biological Chemistry.

[410]  S. Sensi,et al.  Alterations of brain and cerebellar proteomes linked to Aβ and tau pathology in a female triple-transgenic murine model of Alzheimer's disease , 2010, Cell Death and Disease.

[411]  G. Collingridge,et al.  Microtubule-associated protein tau is essential for long-term depression in the hippocampus , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[412]  J. Ávila,et al.  Polymerization of τ into Filaments in the Presence of Heparin: The Minimal Sequence Required for τ ‐ τ Interaction , 1996 .

[413]  E. Masliah,et al.  Cerebrolysin™ efficacy in a transgenic model of tauopathy: role in regulation of mitochondrial structure , 2014, BMC Neuroscience.

[414]  E. Braak,et al.  Distribution, Levels, and Activity of Glycogen Synthase Kinase‐3 in the Alzheimer Disease Brain , 1997, Journal of neuropathology and experimental neurology.

[415]  Yingfu Li,et al.  Tau protein binds single‐stranded DNA sequence specifically – the proof obtained in vitro with non‐equilibrium capillary electrophoresis of equilibrium mixtures , 2005, FEBS letters.

[416]  Q. Tian,et al.  Essential role of tau phosphorylation in adult hippocampal neurogenesis , 2010, Hippocampus.

[417]  L. Wilkinson Immunity , 1891, The Lancet.

[418]  K. Ye,et al.  Human wild-type full-length tau accumulation disrupts mitochondrial dynamics and the functions via increasing mitofusins , 2016, Scientific Reports.

[419]  R. Barbour,et al.  Phosphorylation of Ser-129 Is the Dominant Pathological Modification of α-Synuclein in Familial and Sporadic Lewy Body Disease* , 2006, Journal of Biological Chemistry.

[420]  P. Reddy,et al.  Abnormal interaction between the mitochondrial fission protein Drp1 and hyperphosphorylated tau in Alzheimer's disease neurons: implications for mitochondrial dysfunction and neuronal damage. , 2012, Human molecular genetics.

[421]  Ramesh Kandimalla,et al.  Multiple faces of dynamin-related protein 1 and its role in Alzheimer's disease pathogenesis. , 2016, Biochimica et biophysica acta.

[422]  R. Maccioni,et al.  Tau protein binds to pericentromeric DNA: a putative role for nuclear tau in nucleolar organization , 2006, Journal of Cell Science.

[423]  T. Iwatsubo,et al.  Somatodendritic localization of phosphorylated tau in neonatal and adult rat cerebral cortex , 1997, Neuroreport.

[424]  L. Buée,et al.  Role of the Tau N-terminal region in microtubule stabilization revealed by new endogenous truncated forms , 2015, Scientific Reports.

[425]  J. Lucas,et al.  Altered Machinery of Protein Synthesis in Alzheimer's: From the Nucleolus to the Ribosome , 2016, Brain pathology.

[426]  Jin-Tai Yu,et al.  Autophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy , 2014, Neurobiology of Aging.

[427]  W. Noble,et al.  Tau phosphorylation: the therapeutic challenge for neurodegenerative disease. , 2009, Trends in molecular medicine.

[428]  K. Cain,et al.  CSF tau and tau/Aβ42 predict cognitive decline in Parkinson's disease. , 2015, Parkinsonism & related disorders.

[429]  W Noble,et al.  Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture , 2011, Cell Death and Disease.

[430]  D. Wilson,et al.  Free fatty acids stimulate the polymerization of tau and amyloid beta peptides. In vitro evidence for a common effector of pathogenesis in Alzheimer's disease. , 1997, The American journal of pathology.

[431]  J. Trojanowski,et al.  Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies , 2009, Nature Reviews Drug Discovery.

[432]  W. Scheper,et al.  The unfolded protein response mediates reversible tau phosphorylation induced by metabolic stress , 2014, Cell Death and Disease.

[433]  Jean-Pierre Julien,et al.  Axonal transport deficits and neurodegenerative diseases , 2013, Nature Reviews Neuroscience.

[434]  Yan-wen Zhang,et al.  Tau protein is involved in morphological plasticity in hippocampal neurons in response to BDNF , 2012, Neurochemistry International.

[435]  M. Saraste,et al.  FEBS Lett , 2000 .

[436]  J. Trotter,et al.  Process Outgrowth of Oligodendrocytes Is Promoted by Interaction of Fyn Kinase with the Cytoskeletal Protein Tau , 2002, The Journal of Neuroscience.

[437]  Kit-Yi Leung,et al.  Novel Phosphorylation Sites in Tau from Alzheimer Brain Support a Role for Casein Kinase 1 in Disease Pathogenesis* , 2007, Journal of Biological Chemistry.

[438]  E. Mandelkow,et al.  Microtubule-associated Protein/Microtubule Affinity-regulating Kinase (p110mark) , 1995, The Journal of Biological Chemistry.

[439]  M. Citron,et al.  Constitutive secretion of tau protein by an unconventional mechanism , 2012, Neurobiology of Disease.

[440]  N. Krogan,et al.  Critical Role of Acetylation in Tau-Mediated Neurodegeneration and Cognitive Deficits , 2015, Nature Medicine.

[441]  W. Scheper,et al.  The unfolded protein response is activated in pretangle neurons in Alzheimer's disease hippocampus. , 2009, The American journal of pathology.

[442]  H. Nagaraja,et al.  Tau Isoform Composition Influences Rate and Extent of Filament Formation* , 2012, The Journal of Biological Chemistry.

[443]  H. Akiyama,et al.  Identification of amino‐terminally cleaved tau fragments that distinguish progressive supranuclear palsy from corticobasal degeneration , 2004, Annals of neurology.

[444]  Romana Höftberger,et al.  Endoplasmic Reticulum Stress Features Are Prominent in Alzheimer Disease but Not in Prion Diseases In Vivo , 2006, Journal of neuropathology and experimental neurology.

[445]  U. Sengupta,et al.  Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice , 2011, Molecular Neurodegeneration.

[446]  G. Bloom,et al.  Amyloid-&bgr; signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease , 2013, Journal of Cell Science.

[447]  J. Hardy,et al.  Enhanced Neurofibrillary Degeneration in Transgenic Mice Expressing Mutant Tau and APP , 2001, Science.

[448]  A. Sidhu,et al.  Age-Dependent Effects of A53T Alpha-Synuclein on Behavior and Dopaminergic Function , 2013, PloS one.

[449]  L. Serpell,et al.  Proteasomal degradation of tau protein , 2002, Journal of neurochemistry.

[450]  Jose Viña,et al.  Amyloid-β toxicity and tau hyperphosphorylation are linked via RCAN1 in Alzheimer's disease. , 2011, Journal of Alzheimer's disease : JAD.

[451]  L. McIntosh,et al.  O-GlcNAc modification of tau directly inhibits its aggregation without perturbing the conformational properties of tau monomers. , 2014, Journal of molecular biology.

[452]  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.

[453]  S. Lovestone,et al.  The Importance of Tau Phosphorylation for Neurodegenerative Diseases , 2013, Front. Neurol..

[454]  G. Muntané,et al.  Phosphorylation of tau and α-synuclein in synaptic-enriched fractions of the frontal cortex in Alzheimer’s disease, and in Parkinson’s disease and related α-synucleinopathies , 2008, Neuroscience.

[455]  C. Surridge,et al.  The difference in the binding of phosphatidylinositol distinguishes MAP2 from MAP2C and Tau. , 1994, Biochemistry.

[456]  M. Pérez,et al.  Caspase-Cleaved Tau Impairs Mitochondrial Dynamics in Alzheimer’s Disease , 2018, Molecular Neurobiology.

[457]  M. Noble,et al.  The microtubule binding domain of microtubule-associated protein MAP1B contains a repeated sequence motif unrelated to that of MAP2 and tau , 1989, The Journal of cell biology.

[458]  J. Pasquini,et al.  Defective ubiquitination of cerebral proteins in Alzheimer's disease , 2000, Journal of neuroscience research.

[459]  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.

[460]  M. Cataldi,et al.  Lysosomal dysfunction disrupts presynaptic maintenance and restoration of presynaptic function prevents neurodegeneration in lysosomal storage diseases , 2016, EMBO molecular medicine.

[461]  W. Noble,et al.  Minocycline reduces the development of abnormal tau species in models of Alzheimer's disease , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[462]  R. Zinkowski,et al.  A novel tau transcript in cultured human neuroblastoma cells expressing nuclear tau , 1993, The Journal of cell biology.

[463]  E. Mandelkow,et al.  Toward a unified scheme for the aggregation of tau into Alzheimer paired helical filaments. , 2002, Biochemistry.

[464]  Tudor A. Fulga,et al.  Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo , 2007, Nature Cell Biology.

[465]  B. Hyman,et al.  Caspase activation precedes and leads to tangles , 2010, Nature.

[466]  M. Goedert,et al.  Interaction of tau protein with the dynactin complex , 2007, The EMBO journal.

[467]  C. Harrington,et al.  Staging the pathological assembly of truncated tau protein into paired helical filaments in Alzheimer’s disease , 1996, Acta Neuropathologica.

[468]  M. Ban,et al.  Tau and α‐synuclein in susceptibility to, and dementia in, Parkinson's disease , 2007 .

[469]  P. Davies,et al.  Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms , 2003, Journal of neurochemistry.

[470]  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.

[471]  J. Brion,et al.  Characterisation of cytoskeletal abnormalities in mice transgenic for wild-type human tau and familial Alzheimer's disease mutants of APP and presenilin-1 , 2004, Neurobiology of Disease.

[472]  A. Peters,et al.  Tau accumulation causes mitochondrial distribution deficits in neurons in a mouse model of tauopathy and in human Alzheimer's disease brain. , 2011, The American journal of pathology.

[473]  G. Ugolini,et al.  The Neuronal Microtubule‐Associated Protein Tau Is a Substrate for Caspase‐3 and an Effector of Apoptosis , 2000 .

[474]  O. F. Olesen Proteolytic degradation of microtubule associated protein tau by thrombin. , 1994, Biochemical and biophysical research communications.

[475]  P. Davies,et al.  Passive Immunization with Anti-Tau Antibodies in Two Transgenic Models , 2011, The Journal of Biological Chemistry.

[476]  P. Filipcik,et al.  Truncated tau from sporadic Alzheimer's disease suffices to drive neurofibrillary degeneration in vivo , 2006, FEBS letters.

[477]  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.

[478]  M. Diamond,et al.  Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation* , 2015, The Journal of Biological Chemistry.

[479]  Jason E Gestwicki,et al.  Methylthioninium chloride (methylene blue) induces autophagy and attenuates tauopathy in vitro and in vivo , 2012, Autophagy.

[480]  E. Bigio,et al.  Tau truncation during neurofibrillary tangle evolution in Alzheimer's disease , 2005, Neurobiology of Aging.

[481]  P. Filipcik,et al.  First transgenic rat model developing progressive cortical neurofibrillary tangles , 2012, Neurobiology of Aging.

[482]  K. Jellinger Absence of α-synuclein pathology in postencephalitic parkinsonism , 2009, Acta Neuropathologica.

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

[484]  A. Andreadis,et al.  Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport , 2012, Neurobiology of Aging.

[485]  L. Mucke,et al.  Amyloid-β/Fyn–Induced Synaptic, Network, and Cognitive Impairments Depend on Tau Levels in Multiple Mouse Models of Alzheimer's Disease , 2011, The Journal of Neuroscience.

[486]  M. L. Schmidt,et al.  α-Synuclein in Lewy bodies , 1997, Nature.

[487]  Martin Beibel,et al.  Transmission and spreading of tauopathy in transgenic mouse brain , 2009, Nature Cell Biology.

[488]  J. Cho,et al.  Glycogen Synthase Kinase 3 (cid:1) Induces Caspase-cleaved Tau Aggregation in Situ * , 2022 .

[489]  I. Landrieu,et al.  Identification of O-GlcNAc sites within peptides of the Tau protein and their impact on phosphorylation. , 2011, Molecular bioSystems.

[490]  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.

[491]  William T. Hu,et al.  Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease , 2014, Nature Medicine.

[492]  Adriana B Ferreira,et al.  The Neurotoxic Tau45-230 Fragment Accumulates in Upper and Lower Motor Neurons in Amyotrophic Lateral Sclerosis Subjects , 2016, Molecular medicine.

[493]  S. Brady,et al.  Analysis of isoform-specific tau aggregates suggests a common toxic mechanism involving similar pathological conformations and axonal transport inhibition , 2016, Neurobiology of Aging.

[494]  R. Kayed,et al.  The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration , 2015, Aging cell.

[495]  W. Noble,et al.  Critical residues involved in tau binding to fyn: implications for tau phosphorylation in Alzheimer’s disease , 2016, Acta Neuropathologica Communications.

[496]  Adriana B Ferreira,et al.  The Generation of a 17 kDa Neurotoxic Fragment: An Alternative Mechanism by which Tau Mediates β-Amyloid-Induced Neurodegeneration , 2005, The Journal of Neuroscience.

[497]  T. Shea,et al.  Phosphorylation of Tau Alters Its Association with the Plasma Membrane , 2000, Cellular and Molecular Neurobiology.

[498]  N. Leclerc,et al.  Increased Association Between Rough Endoplasmic Reticulum Membranes and Mitochondria in Transgenic Mice That Express P301L Tau , 2009, Journal of neuropathology and experimental neurology.

[499]  L. Partridge,et al.  Acetylation mimic of lysine 280 exacerbates human Tau neurotoxicity in vivo , 2016, Scientific Reports.

[500]  D. Monard,et al.  Prothrombin mRNA is expressed by cells of the nervous system , 1991, Neuron.

[501]  L. Staudt,et al.  XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. , 2004, Immunity.

[502]  A. Cattaneo,et al.  Nerve growth factor and galantamine ameliorate early signs of neurodegeneration in anti-nerve growth factor mice , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[503]  B. C. Carter,et al.  Multiple-motor based transport and its regulation by Tau , 2007, Proceedings of the National Academy of Sciences.

[504]  J. Ávila,et al.  Thermodynamics of the Interaction between Alzheimer's Disease Related Tau Protein and DNA , 2014, PloS one.

[505]  F. Terro,et al.  Post-translational modifications of tau protein: Implications for Alzheimer's disease , 2011, Neurochemistry International.

[506]  L. Grinberg,et al.  Acetylated tau destabilizes the cytoskeleton in the axon initial segment and is mislocalized to the somatodendritic compartment , 2016, Molecular Neurodegeneration.

[507]  Maxime W. C. Rousseaux,et al.  TRIM28 regulates the nuclear accumulation and toxicity of both alpha-synuclein and tau , 2016, eLife.

[508]  U. Sengupta,et al.  Characterization of tau oligomeric seeds in progressive supranuclear palsy , 2014, Acta neuropathologica communications.

[509]  M. Owen,et al.  Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology , 2013, Molecular Psychiatry.

[510]  L. Gan,et al.  Acetylated tau in Alzheimer's disease: An instigator of synaptic dysfunction underlying memory loss Increased levels of acetylated tau blocks the postsynaptic signaling required for plasticity and promotes memory deficits associated with tauopathy , 2017, BioEssays : news and reviews in molecular, cellular and developmental biology.

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

[512]  D. Hanger,et al.  Direct analysis of tau from PSP brain identifies new phosphorylation sites and a major fragment of N‐terminally cleaved tau containing four microtubule‐binding repeats , 2008, Journal of neurochemistry.

[513]  Ram Dixit,et al.  Differential Regulation of Dynein and Kinesin Motor Proteins by Tau , 2008, Science.

[514]  H. Braak,et al.  Staging of alzheimer's disease-related neurofibrillary changes , 1995, Neurobiology of Aging.

[515]  Xiaomin Song,et al.  Co-immunoprecipitation with Tau Isoform-specific Antibodies Reveals Distinct Protein Interactions and Highlights a Putative Role for 2N Tau in Disease , 2016, The Journal of Biological Chemistry.

[516]  Sonja W. Scholz,et al.  Genome-Wide Association Study reveals genetic risk underlying Parkinson’s disease , 2009, Nature Genetics.

[517]  R. Jope,et al.  Proteolysis of tau by calpain. , 1989, Biochemical and biophysical research communications.

[518]  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.

[519]  J. Freed,et al.  Tau binds to lipid membrane surfaces via short amphipathic helices located in its microtubule-binding repeats. , 2014, Biophysical journal.

[520]  J. Ávila,et al.  Tau isoform with three microtubule binding domains is a marker of new axons generated from the subgranular zone in the hippocampal dentate gyrus: implications for Alzheimer's disease. , 2012, Journal of Alzheimer's disease : JAD.

[521]  E. Sigurdsson,et al.  Passive immunization targeting pathological phospho‐tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain , 2011, Journal of neurochemistry.

[522]  Paul Greengard,et al.  Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies , 2007, Proceedings of the National Academy of Sciences.

[523]  T. Südhof,et al.  CSPα promotes SNARE-complex assembly by chaperoning SNAP-25 during synaptic activity , 2011, Nature Cell Biology.

[524]  F. LaFerla,et al.  Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. , 2007, The American journal of pathology.

[525]  O. Ross,et al.  Association Studies of Sporadic Parkinson’s Disease in the Genomic Era , 2014, Current genomics.

[526]  H. Huttunen,et al.  Internalized Tau sensitizes cells to stress by promoting formation and stability of stress granules , 2016, Scientific Reports.

[527]  T. Shea,et al.  A 26–30 kDa developmentally-regulated tauisoform localized within nuclei of mitotic humanneuroblastoma cells , 1998, International Journal of Developmental Neuroscience.

[528]  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.

[529]  C. Oliveira,et al.  ER stress is involved in Aβ‐induced GSK‐3β activation and tau phosphorylation , 2008, Journal of neuroscience research.

[530]  E. Mandelkow,et al.  Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration , 2011, The EMBO journal.

[531]  L. Petrucelli,et al.  FTDP‐17 with Pick body‐like inclusions associated with a novel tau mutation, p.E372G , 2017, Brain pathology.

[532]  D. Xia,et al.  Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment , 2017, Acta Neuropathologica.

[533]  J. Winn,et al.  Brain , 1878, The Lancet.

[534]  E. Mandelkow,et al.  Cleavage of Tau by calpain in Alzheimer's disease: the quest for the toxic 17 kD fragment , 2011, Neurobiology of Aging.

[535]  D. Bennett,et al.  The neuropathology of older persons with and without dementia from community versus clinic cohorts. , 2009, Journal of Alzheimer's disease : JAD.

[536]  S. A. Hussaini,et al.  Neuronal activity enhances tau propagation and tau pathology in vivo , 2016, Nature Neuroscience.

[537]  M. Mercken,et al.  Differential sensitivity to proteolysis by brain calpain of adult human tau, fetal human tau and PHF‐tau , 1995, FEBS letters.

[538]  L. Buée,et al.  Mutant huntingtin alters Tau phosphorylation and subcellular distribution. , 2015, Human molecular genetics.

[539]  D. Holtzman,et al.  Neuronal activity regulates extracellular tau in vivo , 2014, The Journal of experimental medicine.

[540]  Céline Héraud,et al.  Levels of kinesin light chain and dynein intermediate chain are reduced in the frontal cortex in Alzheimer’s disease: implications for axoplasmic transport , 2011, Acta Neuropathologica.

[541]  A. Gutiérrez,et al.  Soluble phospho-tau from Alzheimer’s disease hippocampus drives microglial degeneration , 2016, Acta Neuropathologica.

[542]  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.

[543]  P. Verstreken,et al.  Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation. , 2015, Cell reports.

[544]  K. Ye,et al.  SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination , 2014, Proceedings of the National Academy of Sciences.

[545]  Peter Holmans,et al.  A potential endophenotype for Alzheimer's disease: cerebrospinal fluid clusterin , 2016, Neurobiology of Aging.

[546]  D. Geschwind,et al.  Degradation of tau protein by puromycin-sensitive aminopeptidase in vitro. , 2006, Biochemistry.

[547]  D. Zheng,et al.  DnaJ/Hsc70 chaperone complexes control the extracellular release of neurodegenerative‐associated proteins , 2016, The EMBO journal.

[548]  R. Ravid,et al.  Proteomic and Functional Analyses Reveal a Mitochondrial Dysfunction in P301L Tau Transgenic Mice* , 2005, Journal of Biological Chemistry.

[549]  B. Ebert,et al.  The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia , 2016, Nature Reviews Cancer.

[550]  T. Gómez-Isla,et al.  A novel GSK-3β inhibitor reduces Alzheimer's pathology and rescues neuronal loss in vivo , 2009, Neurobiology of Disease.

[551]  E. Mandelkow,et al.  Mutations of Tau Protein in Frontotemporal Dementia Promote Aggregation of Paired Helical Filaments by Enhancing Local β-Structure* , 2001, The Journal of Biological Chemistry.

[552]  Bill Bynum,et al.  Lancet , 2015, The Lancet.

[553]  R. Barker,et al.  The role of tau in the pathological process and clinical expression of Huntington’s disease , 2015, Brain : a journal of neurology.