Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a loss of dopaminergic neurons (DN) in the substantia nigra (SN). Several lines of evidence suggest that apoptotic cell death of DN is driven in part by non-cell autonomous mechanisms orchestrated by microglial cell-mediated inflammatory processes. Although the mechanisms and molecular network underlying this deleterious cross-talk between DN and microglial cells remain largely unknown, previous work indicates that, upon DN injury, activation of the β2 integrin subunit CD11b is required for microglia-mediated DN cell death. Interestingly, during brain development, the CD11b integrin is also involved in microglial induction of neuronal apoptosis and has been shown to act in concert with the DAP12 immunoreceptor. Whether such a developmental CD11b/DAP12 pathway could be reactivated in a pathological context such as PD and play a role in microglia-induced DN cell death is a tantalizing hypothesis that we wished to test in this study.
To test the possibility that DAP12 could be involved in microglia-associated DN injury, we used both in vitro and in vivo toxin-based experimental models of PD recapitulating microglial-mediated non-cell autonomous mechanisms of DN cell death. In vitro, enriched mesencephalic neuronal/microglial co-cultures were exposed to the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+) whereas in vivo, mice were administrated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) according to acute or subchronic mode. Mice deficient for DAP12 or CD11b were used to determine the pathological function of the CD11b/DAP12 pathway in our disease models.
Our results show that DAP12 and CD11b partially contribute to microglia-induced DN cell death in vitro. Yet, in vivo, mice deficient for either of these factors develop similar neuropathological alterations as their wild-type counterparts in two different MPTP mouse models of PD.
Overall, our data suggest that DAP12 and CD11b contribute to microglial-induced DN cell death in vitro but not in vivo in the MPTP mouse model of PD. Therefore, the CD11b/DAP12 pathway may not be considered as a promising therapeutic target for PD.