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Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by loss of midbrain dopaminergic (mDA) neurons in the substantia nigra (SN). Microglia-mediated neuroinflammation has been described as a common hallmark of PD and is believed to further trigger the progression of neurodegenerative events. Injections of 6-hydroxydopamine (6-OHDA) are widely used to induce degeneration of mDA neurons in rodents as an attempt to mimic PD and to study neurodegeneration, neuroinflammation as well as potential therapeutic approaches. In the present study, we addressed microglia and astroglia reactivity in the SN and the caudatoputamen (CPu) after 6-OHDA injections into the medial forebrain bundle (MFB), and further analyzed the temporal and spatial expression patterns of pro-inflammatory and anti-inflammatory markers in this mouse model of PD. We provide evidence that activated microglia as well as neurons in the lesioned SN and CPu express Transforming growth factor β1 (Tgfβ1), which overlaps with the downregulation of pro-inflammatory markers Tnfα, and iNos, and upregulation of anti-inflammatory markers Ym1 and Arg1. Taken together, the data presented in this study suggest an important role for Tgfβ1 as a lesion-associated factor that might be involved in regulating microglia activation states in the 6-OHDA mouse model of PD in order to prevent degeneration of uninjured neurons by microglia-mediated release of neurotoxic factors such as Tnfα and nitric oxide (NO).
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by loss of midbrain dopaminergic neurons in the substantia nigra (SN) and the subsequent loss of axonal projections to the caudatoputamen (CPu) resulting in decreased dopamine levels (Jellinger, 2001)
We have demonstrated that microglia quickly adopt a reactive state in the SN and CPu after injection of 6-OHDA into the medial forebrain bundle (MFB)
The rapid microglial response is followed by an astrocytic reaction, which persists until 14 days after injection whereas microglial reactivity decreased and morphological changes of microglia normalize from 6 days onwards
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder that is characterized by loss of midbrain dopaminergic (mDA) neurons in the substantia nigra (SN) and the subsequent loss of axonal projections to the caudatoputamen (CPu) resulting in decreased dopamine levels (Jellinger, 2001). In human PD cases, microglia reactivity has been extensively described (McGeer and McGeer, 2008) Due to their unique origin (Prinz and Priller, 2014), microglia undergo ageing and are believed to become senescent, a phenomenon which is likely to impair their normal functions (Streit, 2006). Injection of 6-OHDA has been shown to result in a rapid decrease in tyrosine hydroxylase (TH)+ fiber densities in the CPu and a delayed apoptotic cell death of TH+ dopaminergic neurons in the midbrain which follows several days after initial injection of the toxin (Martí et al, 2002; Stott and Barker, 2014). We provide evidence that activated microglia as well as neurons in the lesioned SN and CPu express Tgfβ, which precedes the downregulation of pro-inflammatory markers. Our data suggest an important role for Tgfβ as a lesion-associated factor that might regulate expression of inflammatory markers in the 6-OHDA model of PD
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