Dual Mechanism of Toxicity for Extracellular Injection of Tau Oligomers versus Monomers in Human Tau Mice.

The mechanism of tau toxicity is still unclear. Here we report that recombinant tau oligomers and monomers, intraventricularly injected in mice with a pure human tau background, foster tau pathology through different mechanisms. Oligomeric forms of tau alter the conformation of tau in a paired helical filament-like manner. This effect occurs without tau hyperphosphorylation as well as activation of specific kinases, suggesting that oligomers of tau induce tau assembly through a nucleation effect. Monomers, in turn, induce neurodegeneration through a calpain-mediated tau cleavage that leads to accumulation of a 17 kDa neurotoxic peptide and induction of apoptotic cell death.

[1]  M. Tabaton,et al.  Beta‐amyloid 1‐42 monomers, but not oligomers, produce PHF‐like conformation of Tau protein , 2016, Aging cell.

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

[3]  A. Palmeri,et al.  Extracellular Tau Oligomers Produce An Immediate Impairment of LTP and Memory , 2016, Scientific Reports.

[4]  Michel Goedert,et al.  Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein , 2015, Science.

[5]  Jianhua Shi,et al.  Truncation and Activation of Dual Specificity Tyrosine Phosphorylation-regulated Kinase 1A by Calpain I , 2015, The Journal of Biological Chemistry.

[6]  C. Dickey,et al.  Cellular factors modulating the mechanism of tau protein aggregation , 2015, Cellular and Molecular Life Sciences.

[7]  Janna H. Neltner,et al.  Primary age-related tauopathy (PART): a common pathology associated with human aging , 2014, Acta Neuropathologica.

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

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

[10]  C. Jack,et al.  Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers , 2013, The Lancet Neurology.

[11]  Antonio G. García,et al.  Stabilizers of neuronal and mitochondrial calcium cycling as a strategy for developing a medicine for Alzheimer's disease. , 2012, ACS chemical neuroscience.

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

[13]  E. Masliah,et al.  Molecular mechanisms of neurodegeneration in Alzheimer's disease. , 2010, Human molecular genetics.

[14]  Yi Li,et al.  Developmental regulation of tau phosphorylation, tau kinases, and tau phosphatases , 2009, Journal of neurochemistry.

[15]  J. Brioni,et al.  The novel calpain inhibitor A-705253 potently inhibits oligomeric beta-amyloid-induced dynamin 1 and tau cleavage in hippocampal neurons , 2008, Neurochemistry International.

[16]  A. Ferreira,et al.  Caspase-3- and calpain-mediated tau cleavage are differentially prevented by estrogen and testosterone in beta-amyloid-treated hippocampal neurons , 2007, Neuroscience.

[17]  A. Sikorski,et al.  Spectrin and calpain: a ‘target’ and a ‘sniper’ in the pathology of neuronal cells , 2005, Cellular and Molecular Life Sciences CMLS.

[18]  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.

[19]  T. Arendt,et al.  Pseudophosphorylation of tau protein alters its ability for self‐aggregation , 2004, Journal of neurochemistry.

[20]  G. Schellenberg,et al.  Alteration in calcium channel properties is responsible for the neurotoxic action of a familial frontotemporal dementia tau mutation , 2003, Journal of neurochemistry.

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

[22]  F. LaFerla Calcium dyshomeostasis and intracellular signalling in alzheimer's disease , 2002, Nature Reviews Neuroscience.

[23]  I. Grundke‐Iqbal,et al.  Hyperphosphorylation induces self-assembly of τ into tangles of paired helical filaments/straight filaments , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  P. Davies,et al.  Conformational change as one of the earliest alterations of tau in Alzheimer’s disease , 2000, Neurobiology of Aging.

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

[26]  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.

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

[28]  J. Trojanowski,et al.  Biopsy-derived adult human brain tau is phosphorylated at many of the same sites as Alzheimer's disease paired helical filament tau , 1994, Neuron.

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

[30]  P. Calissano,et al.  In vitro cultured neurons for molecular studies correlating apoptosis with events related to Alzheimer disease , 2008, The Cerebellum.