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Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation
Published on: June 26, 2018
Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes
Corinna Bliederhaeuser1, Veselin Grozdanov1, Anna Speidel2
1Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
Abstract:
Extracellular alpha-synuclein (αsyn) oligomers, associated to exosomes or free, play an important role in the pathogenesis of Parkinson's disease (PD). Increasing evidence suggests that these extracellular moieties activate microglia leading to enhanced neuronal damage. Despite extensive efforts on studying neuroinflammation in PD, little is known about the impact of age on microglial activation and phagocytosis, especially of extracellular αsyn oligomers. Here, we show that microglia isolated from adult mice, in contrast to microglia from young mice, display phagocytosis deficits of free and exosome-associated αsyn oligomers combined with enhanced TNFα secretion. In addition, we describe a dysregulation of monocyte subpopulations with age in mice and humans. Accordingly, human monocytes from elderly donors also show reduced phagocytic activity of extracellular αsyn. These findings suggest that these age-related alterations may contribute to an increased susceptibility to pathogens or abnormally folded proteins with age in neurodegenerative diseases.
Insights
Aging impairs microglia's ability to clear extracellular alpha-synuclein (αsyn) oligomers, worsening Parkinson's disease (PD) neuroinflammation. Elderly humans and mice show reduced αsyn phagocytosis, contributing to age-related neurodegeneration susceptibility.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Extracellular alpha-synuclein (αsyn) oligomers are implicated in Parkinson's disease (PD) pathogenesis.
- Microglial activation by αsyn contributes to neuroinflammation and neuronal damage in PD.
- The impact of aging on microglial function regarding αsyn clearance remains poorly understood.
Purpose of the Study:
- To investigate the effect of age on microglial activation and phagocytosis of extracellular αsyn oligomers.
- To examine age-related changes in monocyte subpopulations in mice and humans.
- To determine if age-associated alterations in immune cells impact αsyn clearance.
Main Methods:
- Isolation and analysis of microglia from young and adult mice.
- Assessment of phagocytosis of free and exosome-associated αsyn oligomers by microglia.
- Measurement of TNFα secretion from microglia.
- Analysis of monocyte subpopulations in aged mice and elderly human donors.
- Evaluation of phagocytic activity of human monocytes towards αsyn.
Main Results:
- Microglia from adult mice exhibit reduced phagocytosis of αsyn oligomers compared to young mice.
- Adult microglia show increased TNFα secretion in response to αsyn oligomers.
- Age-related dysregulation of monocyte subpopulations was observed in both mice and humans.
- Elderly human monocytes demonstrated diminished phagocytic capacity for extracellular αsyn.
Conclusions:
- Aging impairs microglial phagocytosis of extracellular αsyn oligomers, potentially exacerbating PD pathology.
- Age-associated changes in immune cells, including monocytes, may increase susceptibility to neurodegenerative diseases.
- These findings highlight the critical role of aging in neuroinflammation and protein aggregation diseases like PD.
