Targeted overexpression of human α-synuclein triggers microglial activation and an adaptive immune response in a mouse model of parkinson disease

Shaji Theodore, Shuwen Cao, Pamela J. McLean, David G. Standaert

Research output: Contribution to journalArticlepeer-review

202 Scopus citations

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 α-synuclein (α-SYN), particularly nitrated species, which are released as a consequence of dopaminergic neurodegeneration. To examine the relationship between α-SYN, microglial activation, and adaptive immunity, we used a mouse model of Parkinson disease in which human α-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 α-SYN alone, in the absence of overt neurodegeneration, is sufficient to trigger neuroinflammation with both microglial activation and stimulation of adaptive immunity.

Original languageEnglish (US)
Pages (from-to)1149-1158
Number of pages10
JournalJournal of Neuropathology and Experimental Neurology
Volume67
Issue number12
DOIs
StatePublished - Dec 2008

Keywords

  • Adeno-associated virus
  • Dopamine
  • Eurodegeneration
  • Euroinflammation
  • Glia
  • Immunoglobulin
  • Lymphocytes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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