title: Targeted overexpression of human alpha-synuclein triggers microglial activation and an adaptive immune response in a mouse model of Parkinson disease.
abstract: Microglial activation and adaptive immunity have been implicated in the neurodegenerative processes in Parkinson disease. It has been proposed that these responses may be triggered by modified forms of alpha-synuclein (alpha-SYN), particularly nitrated species, which are released as a consequence of dopaminergic neurodegeneration. To examine the relationship between alpha-SYN, microglial activation, and adaptive immunity, we used a mouse model of Parkinson disease in which human alpha-SYN is overexpressed by a recombinant adeno-associated virus vector, serotype 2 (AAV2-SYN); this overexpression leads to slow degeneration of dopaminergic neurons. Microglial activation and components of the adaptive immune response were assessed using immunohistochemistry; quantitative polymerase chain reaction was used to examine cytokine expression. Four weeks after injection, there was a marked increase in CD68-positive microglia and greater infiltration of B and T lymphocytes in the substantia nigra pars compacta of the AAV2-SYN group than in controls. At 12 weeks, CD68 staining declined, but B- and T-cell infiltration persisted. Expression of proinflammatory cytokines was enhanced, whereas markers of alternative activation (i.e. arginase I and interleukins 4 and 13) were not altered. Increased immunoreactivity for mouse immunoglobulin was detected at all time points in the AAV2-SYN animals. These data show that overexpression of alpha-SYN alone, in the absence of overt neurodegeneration, is sufficient to trigger neuroinflammation with both microglial activation and stimulation of adaptive immunity.
authors.affiliation: Center for Neurodegeneration and Experimental Therapeutics, The University of Alabama at Birmingham, Alabama 35294-0021, USA.
authors.forename: Shaji
authors.initials: S
authors.lastname: Theodore
authors.forename: Shuwen
authors.initials: S
authors.lastname: Cao
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: McLean
authors.forename: David G
authors.initials: DG
authors.lastname: Standaert
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000276:immunology / Q000378:metabolism; D001921:Brain / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D055633:Immune System Phenomena / Q000276:immunology*; D007136:Immunoglobulins / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology*; D009410:Nerve Degeneration / Q000276:immunology / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D013378:Substantia Nigra / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D014162:Transfection; D051844:alpha-Synuclein / Q000235:genetics / Q000276:immunology*; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D016207:Cytokines; D004298:Dopamine; D007136:Immunoglobulins; D051844:alpha-Synuclein; C081026:CD68 protein, mouse; D000097382:CD68 Molecule