Sources of extracellular tau and its signaling.

The pathology associated with tau protein, tauopathy, has been recently analyzed in different disorders, leading to the suggestion that intracellular and extracellular tau may itself be the principal agent in the transmission and spreading of tauopathies. Tau pathology is based on an increase in the amount of tau, an increase in phosphorylated tau, and/or an increase in aggregated tau. Indeed, phosphorylated tau protein is the main component of tau aggregates, such as the neurofibrillary tangles present in the brain of Alzheimer's disease patients. It has been suggested that intracellular tau could be toxic to neurons in its phosphorylated and/or aggregated form. However, extracellular tau could also damage neurons and since neuronal death is widespread in Alzheimer's disease, mainly among cholinergic neurons, these cells may represent a possible source of extracellular tau. However, other sources of extracellular tau have been proposed that are independent of cell death. In addition, several ways have been proposed for cells to interact with, transmit, and spread extracellular tau, and to transduce signals mediated by this tau. In this work, we will discuss the role of extracellular tau in the spreading of the tau pathology.

[1]  R. Kayed,et al.  Formation and Propagation of Tau Oligomeric Seeds , 2013, Front. Neurol..

[2]  D. Dickson,et al.  Characteristics of TBS-extractable hyperphosphorylated tau species: aggregation intermediates in rTg4510 mouse brain. , 2012, Journal of Alzheimer's disease : JAD.

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

[4]  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.

[5]  B. Hyman,et al.  Soluble forms of tau are toxic in Alzheimer’s disease , 2012, Translational neuroscience.

[6]  N. Leclerc,et al.  Hyperphosphorylation and Cleavage at D421 Enhance Tau Secretion , 2012, PloS one.

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

[8]  J. Falcón-Pérez,et al.  Proteostasis of tau. Tau overexpression results in its secretion via membrane vesicles , 2012, FEBS letters.

[9]  N. Hooper,et al.  Alkaline Phosphatase Is Increased in both Brain and Plasma in Alzheimer’s Disease , 2011, Neurodegenerative Diseases.

[10]  M. Vitek,et al.  Loss of tau elicits axonal degeneration in a mouse model of Alzheimer's disease , 2010, Neuroscience.

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

[12]  J. Trojanowski,et al.  Total and phosphorylated tau protein as biological markers of Alzheimer’s disease , 2010, Experimental Gerontology.

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

[14]  J. Ávila,et al.  Characteristics and consequences of muscarinic receptor activation by tau protein , 2009, European Neuropsychopharmacology.

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

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

[17]  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.

[18]  H. Itoh,et al.  Functions and Regulatory Mechanisms of Gq-Signaling Pathways , 2009, Neurosignals.

[19]  H. Cai,et al.  Activation of protein kinase C modulates BACE1-mediated β-secretase activity , 2008, Neurobiology of Aging.

[20]  K. Ashe,et al.  Accumulation of Pathological Tau Species and Memory Loss in a Conditional Model of Tauopathy , 2007, The Journal of Neuroscience.

[21]  N. Leclerc,et al.  Tau interacts with Golgi membranes and mediates their association with microtubules. , 2006, Cell motility and the cytoskeleton.

[22]  J. Ávila,et al.  Extracellular tau is toxic to neuronal cells , 2006, FEBS letters.

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

[24]  D. Campion,et al.  Tau is not normally degraded by the proteasome , 2005, Journal of neuroscience research.

[25]  Jesus Avila,et al.  Role of tau protein in both physiological and pathological conditions. , 2004, Physiological reviews.

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

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

[28]  Leslie Wilson,et al.  Differential regulation of microtubule dynamics by three- and four-repeat tau: Implications for the onset of neurodegenerative disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  E. Jauch,et al.  C-tau biomarker of neuronal damage in severe brain injured patients: association with elevated intracranial pressure and clinical outcome , 2002, Brain Research.

[30]  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.

[31]  C. Felder.  Muscarinic acetylcholine receptors: signal transduction through multiple effectors , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[32]  J. Growdon,et al.  Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. , 1992, Science.

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

[34]  P. Greengard,et al.  Protein phosphorylation regulates secretion of Alzheimer beta/A4 amyloid precursor protein. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Paul J. Harrison,et al.  Increased tau messenger RNA in Alzheimer's disease hippocampus. , 1990, The American journal of pathology.

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

[37]  P. Davies,et al.  SELECTIVE LOSS OF CENTRAL CHOLINERGIC NEURONS IN ALZHEIMER'S DISEASE , 1976, The Lancet.

[38]  S. Dix,et al.  Oral Sessions: O2-08: Basic Science: Protective and Pathological Protein-Protein Interactions in Alzheimer’s Disease P329 O2-07-04 GENETIC ABLATION OF NRF2 MODULATES ALZHEIMER’S DISEASE–LIKE PATHOLOGY IN APP/PS1 MOUSE , 2013 .

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