title: Early loss of oligodendrocytes in human and experimental neuromyelitis optica lesions.
abstract: Neuromyelitis optica (NMO) is a chronic, mostly relapsing inflammatory demyelinating disease of the CNS characterized by serum anti-aquaporin 4 (AQP4) antibodies in the majority of patients. Anti-AQP4 antibodies derived from NMO patients target and deplete astrocytes in experimental models when co-injected with complement. However, the time course and mechanisms of oligodendrocyte loss and demyelination and the fate of oligodendrocyte precursor cells (OPC) have not been examined in detail. Also, no studies regarding astrocyte repopulation of experimental NMO lesions have been reported. We utilized two rat models using either systemic transfer or focal intracerebral injection of recombinant human anti-AQP4 antibodies to generate NMO-like lesions. Time-course experiments were performed to examine oligodendroglial and astroglial damage and repair. In addition, oligodendrocyte pathology was studied in early human NMO lesions. Apart from early complement-mediated astrocyte destruction, we observed a prominent, very early loss of oligodendrocytes and oligodendrocyte precursor cells (OPCs) as well as a delayed loss of myelin. Astrocyte repopulation of focal NMO lesions was already substantial after 1 week. Olig2-positive OPCs reappeared before NogoA-positive, mature oligodendrocytes. Thus, using two experimental models that closely mimic the human disease, our study demonstrates that oligodendrocyte and OPC loss is an extremely early feature in the formation of human and experimental NMO lesions and leads to subsequent, delayed demyelination, highlighting an important difference in the pathogenesis of MS and NMO.
authors.affiliation: Institute of Neuropathology, University Medical Centre Göttingen, Robert-Koch-Str. 40, 37099, Göttingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Wrzos
authors.forename: Anne
authors.initials: A
authors.lastname: Winkler
authors.forename: Imke
authors.initials: I
authors.lastname: Metz
authors.forename: Dieter M
authors.initials: DM
authors.lastname: Kayser
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Thal
authors.forename: Christiane
authors.initials: C
authors.lastname: Wegner
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.forename: Stefan
authors.initials: S
authors.lastname: Nessler
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Bennett
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001921:Brain / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D004676:Myelin Basic Protein / Q000378:metabolism; D009185:Myelin Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009471:Neuromyelitis Optica / Q000473:pathology*; D000070798:Nogo Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology*; D011917:Rats, Inbred Lew; D013116:Spinal Cord / Q000473:pathology*
chemical_list: D051401:Aquaporin 4; D051792:Basic Helix-Loop-Helix Proteins; D016207:Cytokines; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins; D000070798:Nogo Proteins; D000076104:Oligodendrocyte Transcription Factor 2; C436006:Mbp protein, rat; C522729:Olig2 protein, rat; C000603199:RTN4 protein, human; C000603197:Rtn4 protein, rat