Infiltration of circulating myeloid cells through CD95L contributes to neurodegeneration in mice.
Bottom Line: We show that DN death is not mediated by CD95-induced apoptosis because deletion of CD95 in DNs does not influence MPTP-induced neurodegeneration.In contrast, deletion of CD95L in peripheral myeloid cells significantly protects against MPTP neurotoxicity and preserves striatal dopamine levels.Systemic pharmacological inhibition of CD95L dampens the peripheral innate response, reduces the accumulation of infiltrating myeloid cells, and efficiently prevents MPTP-induced DN death.
Affiliation: Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.Show MeSH
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Mentions: To test this hypothesis, we treated WT mice with a stable CD95-Fc fusion protein that neutralizes CD95 activity and does not cross the BBB (CD95-Fc hereafter referred to as APG112; Fig. 3 A). Accordingly, APG112 was not detected in the brain tissue of MPTP-treated mice but only endovascular in the brain of MPTP + APG–treated mice (not depicted). Thus, the CD95-Fc main site of action is in the periphery, and therefore, it can be used to distinguish between the contribution of neurodegeneration of peripheral myeloid cells and resident microglia. 6 d after the last MPTP injection, we analyzed brains and blood of saline- and MPTP-treated mice. Mice that received saline showed a significant reduction of DNs upon MPTP intoxication, whereas, similar to CD95Lf/f;LysMcre mice, mice that had been systemically treated with APG112 were resistant to MPTP-induced degeneration of SNpc DNs. Altogether, these data demonstrate that CD95L neutralization is neuroprotective in a mouse model of DN degeneration (Fig. 3, B and C).
Affiliation: Division of Molecular Neurobiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.