Abnormal deposition of alpha-synuclein in neurons and glia is implicated in many neurological diseases, such as Parkinson's disease and Dementia with Lewy bodies. Recently, evidence has emerged that this protein and its aggregates are secreted from neuronal cells, and this extracellular protein may contribute to the pathogenic process. Here, we show that all the major brain cell types (neurons, astrocytes, and microglia) are capable of clearing the extracellular alpha-synuclein aggregates by internalization and degradation. Among these cell types, microglia showed the highest rate of degradation. Upon activation by lipopolysaccharide, the degradation of the internalized alpha-synuclein aggregates was slowed, causing protein accumulation in the microglial cytoplasm. These results suggest that microglia may be the major scavenger cells for extracellular alpha-synuclein aggregates in brain parenchyma, and that clearance may be regulated by the activation state of these cells. (C) 2008 Elsevier Inc. All Fights reserved.