Tau pathophysiology in neurodegeneration: a tangled issue

Neurodegenerative tauopathies are marked by their common pathologic feature of aggregates formed of hyperphosphorylated tau protein, which are associated with synapse and neuronal loss. Changes in tau conformation result in both loss of normal function and gain of fibrillogenicity that leads to aggregation. Here, we discuss the pathophysiology of tau and emerging evidence of how changes in this protein might ultimately lead to neuronal death. In particular, based on recent evidence, we propose that a non-apoptotic caspase-associated form of death is occurring in tauopathy.

[1]  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.

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

[3]  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.

[4]  P. Bedford.  Adverse cerebral effects of anaesthesia on old people. , 1955, Lancet.

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

[6]  M. Hengartner,et al.  Apoptotic cell death: from worms to wombats ... but what about the weeds? , 2021, Symposia of the Society for Experimental Biology.

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

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

[9]  M. Kirschner,et al.  Tau protein binds to microtubules through a flexible array of distributed weak sites , 1991, The Journal of cell biology.

[10]  J. Kuret,et al.  Evaluating triggers and enhancers of tau fibrillization , 2005, Microscopy research and technique.

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

[12]  M. Hutton.  Molecular genetics of chromosome 17 tauopathies , 2000, Neurobiology of Aging.

[13]  A. Delacourte,et al.  Different distribution of phosphorylated tau protein isoforms in Alzheimer's and Pick's diseases , 1997, FEBS letters.

[14]  T. Arendt,et al.  Hibernation model of tau phosphorylation in hamsters: selective vulnerability of cholinergic basal forebrain neurons – implications for Alzheimer's disease , 2007, The European journal of neuroscience.

[15]  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 .

[16]  S. DeKosky,et al.  Structural correlates of cognition in dementia: quantification and assessment of synapse change. , 1996, Neurodegeneration : a journal for neurodegenerative disorders, neuroprotection, and neuroregeneration.

[17]  M. Mattson,et al.  Intranasal NAP administration reduces accumulation of amyloid peptide and tau hyperphosphorylation in a transgenic mouse model of Alzheimer's disease at early pathological stage , 2007, Journal of Molecular Neuroscience.

[18]  K. Imahori,et al.  Tau protein kinase II is involved in the regulation of the normal phosphorylation state of tau protein. , 1993, Journal of neurochemistry.

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

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

[21]  M. Hutton,et al.  Phenotypic correlations in FTDP-17 , 2001, Neurobiology of Aging.

[22]  G. Johnson,et al.  Tau phosphorylation: physiological and pathological consequences. , 2005, Biochimica et biophysica acta.

[23]  R. Nelson,et al.  Anesthesia Leads to Tau Hyperphosphorylation through Inhibition of Phosphatase Activity by Hypothermia , 2007, The Journal of Neuroscience.

[24]  G. Johnson,et al.  Tau phosphorylation during apoptosis of human SH-SY5Y neuroblastoma cells , 2001, Brain Research.

[25]  E. Head,et al.  Lack of Pathology in a Triple Transgenic Mouse Model of Alzheimer's Disease after Overexpression of the Anti-Apoptotic Protein Bcl-2 , 2008, The Journal of Neuroscience.

[26]  C. W. Scott,et al.  Phosphorylation of tau by proline-directed protein kinase (p34cdc2/p58cyclin A) decreases tau-induced microtubule assembly and antibody SMI33 reactivity , 1993, Brain Research.

[27]  L. Thal,et al.  Genetic evidence for the involvement of τ in progressive supranuclear palsy , 1997, Annals of neurology.

[28]  P. Cohen,et al.  p42 map kinase phosphorylation sites in microtubule‐associated protein tau are dephosphorylated by protein phosphatase 2A1 Implications for Alzheimer's disease , 1992, FEBS letters.

[29]  F. Bonnel,et al.  Exposure to anaesthetic agents, cognitive functioning and depressive symptomatology in the elderly. , 2001, The British journal of psychiatry : the journal of mental science.

[30]  Wolfgang Härtig,et al.  Reversible Paired Helical Filament-Like Phosphorylation of Tau Is an Adaptive Process Associated with Neuronal Plasticity in Hibernating Animals , 2003, The Journal of Neuroscience.

[31]  R. DeTeresa,et al.  Some morphometric aspects of the brain in senile dementia of the alzheimer type , 1981, Annals of neurology.

[32]  M. Goedert,et al.  A Century of Alzheimer's Disease , 2006, Science.

[33]  I. Grundke‐Iqbal,et al.  Polymerization of hyperphosphorylated tau into filaments eliminates its inhibitory activity. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

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

[35]  Hirotaka Yoshida,et al.  Abundant Tau Filaments and Nonapoptotic Neurodegeneration in Transgenic Mice Expressing Human P301S Tau Protein , 2002, The Journal of Neuroscience.

[36]  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.

[37]  Alexandra Flemming,et al.  Infectious disease: Unravelling SARS lethality , 2005, Nature Reviews Drug Discovery.

[38]  H. J. Gamble.  Trends in Neurosciences , 1980 .

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

[40]  D. Dickson,et al.  Apoptosis in oligodendrocytes is associated with axonal degeneration in P301L tau mice , 2004, Neurobiology of Disease.

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

[42]  I Litvan,et al.  Association of an extended haplotype in the tau gene with progressive supranuclear palsy. , 1999, Human molecular genetics.

[43]  B. Boeve,et al.  Refining frontotemporal dementia with parkinsonism linked to chromosome 17: introducing FTDP-17 (MAPT) and FTDP-17 (PGRN). , 2008, Archives of neurology.

[44]  D. Dickson,et al.  Neurofibrillary tangle-related synaptic alterations of spinal motor neurons of P301L tau transgenic mice , 2006, Neuroscience Letters.

[45]  M. Tabaton,et al.  Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy , 2000, Annals of neurology.

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

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

[48]  Aidong Yuan,et al.  Axonal Transport Rates In Vivo Are Unaffected by Tau Deletion or Overexpression in Mice , 2008, The Journal of Neuroscience.

[49]  M. Maloney,et al.  Cofilin-mediated neurodegeneration in alzheimer’s disease and other amyloidopathies , 2007, Molecular Neurobiology.

[50]  E. Mandelkow,et al.  Inducible Expression of Tau Repeat Domain in Cell Models of Tauopathy , 2006, Journal of Biological Chemistry.

[51]  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.

[52]  J. Goldman.  The Association of Actin with Hirano Bodies , 1983, Journal of neuropathology and experimental neurology.

[53]  Hideyuki Yamamoto,et al.  Dephosphorylation of r Factor by Protein Phosphatase 2A in Synaptosomal Cytosol Fractions, and Inhibition by Aluminum , 1990, Journal of neurochemistry.

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

[55]  R. Brandt,et al.  Conversion of Serine to Aspartate Imitates Phosphorylation-induced Changes in the Structure and Function of Microtubule-associated Protein Tau* , 1997, The Journal of Biological Chemistry.

[56]  J. Hardy,et al.  Clinical and pathological features of an Alzheimer's disease patient with the MAPT ΔK280 mutation , 2009, Neurobiology of Aging.

[57]  G. Ugolini,et al.  Apoptotic effect of caspase-3 cleaved tau in hippocampal neurons and its potentiation by tau FTDP-mutation N279K. , 2005, Journal of Alzheimer's disease : JAD.

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

[59]  P. Coleman,et al.  Synaptic slaughter in Alzheimer’s disease , 2003, Neurobiology of Aging.

[60]  K. Imahori,et al.  τ Protein Kinase II Is Involved in the Regulation of the Normal Phosphorylation State of τ Protein , 1993 .

[61]  P. Hof,et al.  Cell-Cycle Reentry and Cell Death in Transgenic Mice Expressing Nonmutant Human Tau Isoforms , 2005, The Journal of Neuroscience.

[62]  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.

[63]  R. Wade-Martins,et al.  Functional MAPT haplotypes: Bridging the gap between genotype and neuropathology , 2007, Neurobiology of Disease.

[64]  P. Cohen,et al.  Identification of a calmodulin‐dependent glycogen synthase kinase in rabbit skeletal muscle, distinct from phosphorylase kinase , 1982, FEBS letters.

[65]  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.

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

[67]  A. Grover,et al.  5′ Splice Site Mutations in tau Associated with the Inherited Dementia FTDP-17 Affect a Stem-Loop Structure That Regulates Alternative Splicing of Exon 10* , 1999, The Journal of Biological Chemistry.

[68]  P. Aisen,et al.  A Neuronal Microtubule-Interacting Agent, NAPVSIPQ, Reduces Tau Pathology and Enhances Cognitive Function in a Mouse Model of Alzheimer's Disease , 2008, Journal of Pharmacology and Experimental Therapeutics.

[69]  G. Johnson,et al.  Activation of glycogen synthase kinase 3beta promotes the intermolecular association of tau. The use of fluorescence resonance energy transfer microscopy. , 2007, The Journal of biological chemistry.

[70]  R. Maccioni,et al.  Subpopulations of tau interact with microtubules and actin filaments in various cell types , 1995, Cell biochemistry and function.

[71]  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.

[72]  B. Hyman,et al.  Coordinated Expression of Caspase 8, 3 and 7 mRNA in Temporal Cortex of Alzheimer Disease: Relationship to Formic Acid Extractable A&bgr;42 Levels , 2006, Journal of neuropathology and experimental neurology.

[73]  E. Mandelkow,et al.  Missorting of Tau in Neurons Causes Degeneration of Synapses That Can Be Rescued by the Kinase MARK2/Par-1 , 2007, The Journal of Neuroscience.

[74]  A. Alzheimer.  Uber eine eigenartige Erkrankung der Hirnrinde , 1907 .

[75]  E. Mandelkow,et al.  Inhibition of APP Trafficking by Tau Protein Does Not Increase the Generation of Amyloid‐β Peptides , 2006, Traffic.

[76]  K. Imahori,et al.  A cdc2‐related kinase PSSALRE/cdk5 is homologous with the 30 kDa subunit of tau protein kinase II, a proline‐directed protein kinase associated with microtubule , 1993, FEBS letters.

[77]  Molecular genetics of chromosome 17 tauopathies , 2000, Neurobiology of Aging.

[78]  S. Maeda,et al.  Increased levels of granular tau oligomers: An early sign of brain aging and Alzheimer's disease , 2006, Neuroscience Research.

[79]  E. Mandelkow,et al.  Abnormal Alzheimer‐like phosphorylation of tau‐protein by cyclin‐dependent kinases cdk2 and cdk5 , 1993, FEBS letters.

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

[81]  L. Qiang,et al.  Neuronal microtubules: when the MAP is the roadblock. , 2005, Trends in cell biology.

[82]  A. Delacourte.  Tau, a biological marker of neurodegenerative diseases. , 2008, Handbook of clinical neurology.

[83]  Jen‐Shin Song,et al.  Tau protein kinase I/GSK-3Β/kinase FA in heparin phosphorylates tau on Ser199, Thr231, Ser235, Ser262, Ser369, and Ser400 sites phosphorylated in Alzheimer disease brain , 1995, Journal of protein chemistry.

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

[85]  C. Cotman,et al.  Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer's disease. , 2001, The American journal of pathology.

[86]  K. Ishiguro,et al.  Tau protein kinase II has a similar characteristic to cdc2 kinase for phosphorylating neurofilament proteins. , 1993, Journal of Biological Chemistry.

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

[88]  I. Vincent,et al.  The cell cycle and human neurodegenerative disease. , 2003, Progress in cell cycle research.

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

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

[91]  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.

[92]  B. Hyman,et al.  Region-specific dissociation of neuronal loss and neurofibrillary pathology in a mouse model of tauopathy. , 2006, The American journal of pathology.

[93]  K. Kosik,et al.  Structure and novel exons of the human tau gene. , 1992, Biochemistry.

[94]  D. Selkoe,et al.  Natural oligomers of the amyloid-β protein specifically disrupt cognitive function , 2005, Nature Neuroscience.

[95]  A Hirano,et al.  Hirano bodies and related neuronal inclusions , 1994, Neuropathology and applied neurobiology.

[96]  M. Hutton.  Missense and splice site mutations in tau associated with FTDP-17: Multiple pathogenic mechanisms , 2001, Neurology.

[97]  A. Faissner,et al.  Tau Binds to the Distal Axon Early in Development of Polarity in a Microtubule- and Microfilament-Dependent Manner , 1996, The Journal of Neuroscience.

[98]  P. Lampert,et al.  Fine structure of the Pick and Hirano bodies in a case of Pick's disease , 1968, Acta Neuropathologica.

[99]  George M. Church,et al.  Single molecule profiling of tau gene expression in Alzheimer’s disease , 2007, Journal of neurochemistry.

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

[101]  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.

[102]  B. Hyman,et al.  Transcriptional and conformational changes of the tau molecule in Alzheimer's disease. , 2005, Biochimica et biophysica acta.

[103]  Andrew W. Kinley,et al.  β-Secretase-Cleaved Amyloid Precursor Protein Accumulates at Actin Inclusions Induced in Neurons by Stress or Amyloid β: A Feedforward Mechanism for Alzheimer's Disease , 2005, The Journal of Neuroscience.

[104]  E. Mandelkow,et al.  Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses , 2003, Neurobiology of Aging.

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

[106]  E. Mandelkow,et al.  Dephosphorylation of tau protein and Alzheimer paired helical filaments by calcmeurin and phosphatase‐2A , 1993, FEBS letters.

[107]  B. Ghetti,et al.  Cell-cycle markers in a transgenic mouse model of human tauopathy: increased levels of cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1. , 2006, The American journal of pathology.

[108]  Michael P. Mazanetz,et al.  Untangling tau hyperphosphorylation in drug design for neurodegenerative diseases , 2007, Nature Reviews Drug Discovery.

[109]  A. Takashima,et al.  Active c‐jun N‐terminal kinase induces caspase cleavage of tau and additional phosphorylation by GSK‐3β is required for tau aggregation , 2008, The European journal of neuroscience.

[110]  Phillip B. Jones,et al.  In Vivo Imaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons , 2008, The Journal of Neuroscience.

[111]  G. Schellenberg,et al.  Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

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

[113]  Joshua M. Shulman,et al.  Tauopathy in Drosophila: Neurodegeneration Without Neurofibrillary Tangles , 2001, Science.

[114]  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.