Microglia Acquire Distinct Activation Profiles Depending on the Degree of α-Synuclein Neuropathology in a rAAV Based Model of Parkinson's Disease

Abstract

Post-mortem analysis of brains from Parkinson's disease (PD) patients strongly supports microglia activation and adaptive immunity as factors contributing to disease progression. Such responses may be triggered by α-synuclein (α-syn), which is known to be the main constituent of the aggregated proteins found in Lewy bodies in the brains of PD patients. To investigate this we used a recombinant viral vector to express human α-syn in rat midbrain at levels that induced neuronal pathology either in the absence or the presence of dopaminergic cell death, thereby mimicking early or late stages of the disease. Microglia activation was assessed by stereological quantification of Mac1+ cells, as well as the expression patterns of CD68 and MCH II. In our study, when α-syn induced neuronal pathology but not cell death, a fast transient increase in microglia cell numbers resulted in the long-term induction of MHC II+ microglia, denoting antigen-presenting ability. On the other hand, when α-syn induced both neuronal pathology and cell death, there was a delayed increase in microglia cell numbers, which correlated with long-lasting CD68 expression and a morphology reminiscent of peripheral macrophages. In addition T-lymphocyte infiltration, as judged by the presence of CD4+ and CD8+ cells, showed distinct kinetics depending on the degree of neurodegeneration, and was significantly higher when cell death occurred. We have thus for the first time shown that the microglial response differs depending on whether α-syn expression results on cell death or not, suggesting that microglia may play different roles during disease progression. Furthermore, our data suggest that the microglial response is modulated by early events related to α-syn expression in substantia nigra and persists at the long term.

Abrogation of α-synuclein–mediated dopaminergic neurodegeneration in LRRK2-deficient rats

“…Microglial activation has been previously described in rAAV2-α-synuclein-transduced rodents (12,14,17). In WT rats transduced with α-synuclein, we observed a significant recruitment of CD68-positive cells within the SNpc (Fig.…”

CD200 fusion protein decreases microglial activation in the hippocampus of aged rats

“…The interaction of CD200 with its receptor is known to contribute to the maintenance of macrophages and microglia in a quiescent state and, conversely, a deficit in CD200 is associated with activation of these cells (Barclay et al, 2002;Hoek et al, 2000;Shinohara et al, 2005). Here, an age-related decrease in hippocampal expression of CD200 is described and this is accompanied by increased expression of several markers of microglial activation.…”

“…Here, we report that expression of MHCII and CD40, as well as iNOS and the chemokines, were similar in hippocampal tissue prepared from aged CD200Fc-treated rats and young rats; the effect of CD200Fc on these markers was rapid, observed only 3 hours following treatment. The mechanism underlying this remains to be established, but it is known that CD200R activation rapidly initiates a cascade of signalling events, including activation of Dok1 and Dok2 negatively regulating Ras-ERK signaling and microglial/macrophage activation in response to TLR4 activation (Shinohara et al, 2005). However, whether these signalling events are important in modulation of microglial activation by CD200Fc require investigation.…”

Dysfunction of two lysosome degradation pathways of α-synuclein in Parkinson’s disease: potential therapeutic targets?

“…to dopaminergic neurotoxicity has been demonstrated in several recent studies in vivo [10,11] . Intracellular and extracellular α-syn are necessarily connected; the disruption of intracellular α-syn degradation causes its extracellular secretion.…”