title: Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation.
abstract: Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule-associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau-induced axonal damage on the potential for remyelination is unknown. Therefore, we investigated OPC differentiation in human P301S tau (P301S-htau) transgenic mice, both in vitro and in vivo following focal demyelination. In 2-month-old P301S-htau mice, which show hyperphosphorylated tau in neurons, we found atrophic axons in the spinal cord in the absence of prominent axonal degeneration. These signs of early axonal damage were associated with microgliosis and an upregulation of IL-1β and TNFα. Following in vivo focal white matter demyelination we found that OPCs differentiated more efficiently in P301S-htau mice than wild type (Wt) mice. We also found an increased level of myelin basic protein within the lesions, which however did not translate into increased remyelination due to higher susceptibility of P301S-htau axons to demyelination-induced degeneration compared to Wt axons. In vitro experiments confirmed higher differentiation capacity of OPCs from P301S-htau mice compared with Wt mice-derived OPCs. Because the OPCs from P301S-htau mice do not ectopically express the transgene, and when isolated from newborn mice behave like Wt mice-derived OPCs, we infer that their enhanced differentiation capacity must have been acquired through microenvironmental priming. Our data suggest the intriguing concept that damaged axons may signal to OPCs and promote their differentiation in the attempt at rescue by remyelination.
authors.affiliation: Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge, Cambridge CB2 0AH, United Kingdom.
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ossola
authors.affiliation: Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge, Cambridge CB2 0AH, United Kingdom.|Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AH, United Kingdom.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge, Cambridge CB2 0AH, United Kingdom.
authors.forename: Alastair
authors.initials: A
authors.lastname: Compston
authors.affiliation: Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge, Cambridge CB2 0AH, United Kingdom.|Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AH, United Kingdom.|NIHR Biomedical Research Centre, Cambridge, CB2 0AH, United Kingdom.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pluchino
authors.affiliation: Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge, Cambridge CB2 0AH, United Kingdom.|Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 0AH, United Kingdom.
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.affiliation: Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge, Cambridge CB2 0AH, United Kingdom.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Spillantini
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D003711:Demyelinating Diseases / Q000209:etiology / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D004676:Myelin Basic Protein / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000150:complications; D013234:Stem Cells / Q000502:physiology*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D039481:CD11b Antigen; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D016875:tau Proteins; C522729:Olig2 protein, rat
keywords: OPCs axons communication; OPCs priming; axonal damage; inflammation; microgliosis; regenerative environment; remyelination; tau pathology