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Temporal evolution of microglia and α-synuclein accumulation following foetal grafting in Parkinson's disease
C Warren Olanow1,2, Mari Savolainen3, Yaping Chu3
1Department of Neurology and Department of Neuroscience, Mount Sinai School of Medicine, New York, NY, USA.
Abstract:
We observed Lewy pathology in healthy embryonic dopamine neurons implanted into the striatum of patients with advanced Parkinson's disease. In the present study we examined the temporal relationship between the presence of inflammation with activated microglia and the emergence of α-synuclein pathology. Inflammation with activated microglia was observed in all grafts and at all time points examined between 18 months and 16 years as determined by both CD45 and TMEM119 staining. In contrast, α-synuclein was not detected at 18 months, only diffuse monomeric α-synuclein staining was observed at 4 years, and α-synuclein aggregates were not observed until 14-16 years after transplantation. Thus, there is evidence of inflammation and microglial activation in graft deposits long before the accumulation of α-synuclein pathology in implanted dopamine neurons. These observations raise the possibility that microglial activation contributes to the development of α-synuclein pathology, and supports the concept that microglia play an integral role in the propagation and spread of α-synuclein pathology.
Insights
Inflammation and activated microglia were present in all Parkinson's disease grafts long before alpha-synuclein pathology emerged. This suggests microglia may contribute to the development and spread of alpha-synuclein aggregation in transplanted neurons.
Area of Science:
- Neuroscience
- Pathology
- Immunology
Background:
- Parkinson's disease (PD) is characterized by Lewy pathology, including alpha-synuclein aggregates.
- Dopamine neuron transplantation is a potential therapy for PD, but graft pathology is a concern.
- The temporal relationship between inflammation and alpha-synuclein pathology in grafts is not well understood.
Purpose of the Study:
- To investigate the temporal link between microglial activation and alpha-synuclein pathology in human embryonic dopamine neuron grafts in PD patients.
- To determine if inflammation precedes or coincides with the development of Lewy pathology in transplanted neurons.
Main Methods:
- Analysis of human embryonic dopamine neuron grafts implanted into the striatum of PD patients.
- Immunohistochemical staining for activated microglia (CD45, TMEM119) and alpha-synuclein at various time points (18 months to 16 years post-transplantation).
Main Results:
- Inflammation and activated microglia were consistently observed in all grafts across all time points (18 months to 16 years).
- Alpha-synuclein pathology was absent at 18 months, diffuse at 4 years, and aggregated only at 14-16 years post-transplantation.
- Inflammation and microglial activation were evident significantly before the accumulation of alpha-synuclein aggregates.
Conclusions:
- Microglial activation and inflammation are early and persistent events in dopamine neuron grafts in PD.
- These findings suggest that microglial activation may play a crucial role in the initiation and progression of alpha-synuclein pathology in transplanted neurons.
- The study supports the hypothesis that microglia are involved in the propagation and spread of alpha-synuclein pathology, a key process in Parkinson's disease.