Relationship between tau pathology and neuroinflammation in Alzheimer's disease.

Alzheimer's disease is a chronic, age-related neurodegenerative disorder. Neurofibrillary tangles are among the pathological hallmarks of Alzheimer's disease. Neurofibrillary tangles consist of abnormal protein fibers known as paired helical filaments. The accumulation of paired helical filaments is one of the most characteristic cellular changes in Alzheimer's disease. Tau protein, a microtubule-associated protein, is the major component of paired helical filaments. Tau in paired helical filaments is hyperphosphorylated, truncated, and aggregated. What triggers the formation of paired helical filaments is not known, but neuroinflammation could play a role. Neuroinflammation is an active process detectable in the earliest stages of Alzheimer's disease. The neuronal toxicity associated with inflammation makes it a potential risk factor in the pathogenesis of Alzheimer's disease. Determining the sequence of events that lead to this devastating disease has become one of the most important goals for the prevention and treatment of Alzheimer's disease. In this review, we focus on the pathological properties of tau thought to play a role in neurofibrillary tangle formation and summarize how central nervous system inflammation might be a critical contributor to the pathology of Alzheimer's disease. A better understanding of the mechanisms that cause neurofibrillary tangle formation is of clinical importance for developing therapeutic strategies to prevent and treat Alzheimer's disease. One of the major challenges facing us is singling out neuroinflammation as a therapeutic target for the prevention of Alzheimer's disease neurodegeneration. The challenge is developing therapeutic strategies that prevent neurotoxicity linked to inflammation without compromising its neuroprotective role.

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

[2]  Lisette Arnaud,et al.  Proteasome–caspase–cathepsin sequence leading to tau pathology induced by prostaglandin J2 in neuronal cells , 2009, Journal of neurochemistry.

[3]  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.

[4]  M. Sastre,et al.  Interactions between APP secretases and inflammatory mediators , 2008, Journal of Neuroinflammation.

[5]  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.

[6]  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.

[7]  J. Israelachvili,et al.  Complementary dimerization of microtubule-associated tau protein: Implications for microtubule bundling and tau-mediated pathogenesis , 2008, Proceedings of the National Academy of Sciences.

[8]  L. Petrucelli,et al.  Akt and CHIP coregulate tau degradation through coordinated interactions , 2008, Proceedings of the National Academy of Sciences.

[9]  Xiao Zhen Zhou,et al.  The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease , 2007, Nature Reviews Molecular Cell Biology.

[10]  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.

[11]  P. Mcgeer,et al.  Therapeutic approaches to inflammation in neurodegenerative disease , 2007, Current opinion in neurology.

[12]  G. Forloni,et al.  JNK signalling: a possible target to prevent neurodegeneration. , 2007, Current pharmaceutical design.

[13]  Patrick L. McGeer,et al.  NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies , 2007, Neurobiology of Aging.

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

[15]  R. Liem,et al.  CHIP-ping away at tau. , 2007, The Journal of clinical investigation.

[16]  Yong J. Lee,et al.  Differential activation of the JNK signal pathway by UV irradiation and glucose deprivation. , 2007, Cellular signalling.

[17]  Bin Zhang,et al.  Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model , 2007, Neuron.

[18]  E. Mandelkow,et al.  Structural Principles of Tau and the Paired Helical Filaments of Alzheimer’s Disease , 2007, Brain pathology.

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

[20]  N. Robakis,et al.  It May Take Inflammation, Phosphorylation and Ubiquitination to ‘Tangle’ in Alzheimer’s Disease , 2007, Neurodegenerative Diseases.

[21]  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.

[22]  P. Fraser,et al.  Small Ubiquitin-like Modifier (SUMO) Modification of Natively Unfolded Proteins Tau and α-Synuclein* , 2006, Journal of Biological Chemistry.

[23]  M. Mattson,et al.  Protein twists and turns in Alzheimer disease , 2006, Nature Medicine.

[24]  R. Takahashi,et al.  In vivo evidence of CHIP up‐regulation attenuating tau aggregation , 2005, Journal of neurochemistry.

[25]  Daniel Kaganovich,et al.  Protein quality control: chaperones culling corrupt conformations , 2005, Nature Cell Biology.

[26]  M. W. Wooten,et al.  Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation , 2005, Journal of neurochemistry.

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

[28]  J. Götz,et al.  Amyloid-induced neurofibrillary tangle formation in Alzheimer's disease: insight from transgenic mouse and tissue-culture models , 2004, International Journal of Developmental Neuroscience.

[29]  E. Mandelkow,et al.  MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons , 2004, The Journal of cell biology.

[30]  D. Dickson.  Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect? , 2004, The Journal of clinical investigation.

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

[32]  Erica S. Johnson,et al.  Protein modification by SUMO. , 2004, Annual review of biochemistry.

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

[34]  Anne Eckert,et al.  Mitochondrial dysfunction, apoptotic cell death, and Alzheimer's disease. , 2003, Biochemical pharmacology.

[35]  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.

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

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

[38]  Y. Liou,et al.  Proline-directed phosphorylation and isomerization in mitotic regulation and in Alzheimer's Disease. , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

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

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

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

[42]  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.

[43]  Ssang-Goo Cho,et al.  Apoptotic signaling pathways: caspases and stress-activated protein kinases. , 2002, Journal of biochemistry and molecular biology.

[44]  C. Pickart,et al.  Inhibition of the ubiquitin-proteasome system in Alzheimer's disease. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

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

[46]  P. Davies,et al.  The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein , 1999, Nature.

[47]  M. Goedert,et al.  Tau protein pathology in neurodegenerative diseases , 1998, Trends in Neurosciences.

[48]  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.

[49]  E. Mandelkow,et al.  The endogenous and cell cycle-dependent phosphorylation of tau protein in living cells: implications for Alzheimer's disease. , 1998, Molecular biology of the cell.

[50]  F. Grosveld,et al.  Frameshift mutants of beta amyloid precursor protein and ubiquitin-B in Alzheimer's and Down patients. , 1998, Science.

[51]  M. Billingsley,et al.  Regulated phosphorylation and dephosphorylation of tau protein: effects on microtubule interaction, intracellular trafficking and neurodegeneration. , 1997, The Biochemical journal.

[52]  K. Kosik,et al.  Cellular Signaling Pathways and Cytoskeletal Organization , 1996, Annals of the New York Academy of Sciences.

[53]  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.

[54]  I. Grundke‐Iqbal,et al.  Cytosolic abnormally hyperphosphorylated tau but not paired helical filaments sequester normal MAPs and inhibit microtubule assembly. , 2008, Journal of Alzheimer's disease : JAD.

[55]  Akihiko Takashima,et al.  GSK-3 is essential in the pathogenesis of Alzheimer's disease. , 2006, Journal of Alzheimer's disease : JAD.

[56]  J. Geddes,et al.  Proteasome or calpain inhibition does not alter cellular tau levels in neuroblastoma cells or primary neurons. , 2005, Journal of Alzheimer's disease : JAD.

[57]  G. Perry,et al.  Tau phosphorylation and assembly. , 2004, Acta neurobiologiae experimentalis.

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

[59]  H. Braak,et al.  Localization of active forms of C-jun kinase (JNK) and p38 kinase in Alzheimer's disease brains at different stages of neurofibrillary degeneration. , 2001, Journal of Alzheimer's disease : JAD.

[60]  M. Goedert,et al.  The repeat region of microtubule-associated protein tau forms part of the core of the paired helical filament of Alzheimer's disease. , 1989, Annals of medicine.