Human pericytes degrade diverse α-synuclein aggregates

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Parkinson's disease (PD) involves alpha-synuclein (α-syn) aggregate accumulation and spread, leading to neurodegeneration.
• Non-neuronal cells, including brain pericytes, are implicated in PD pathogenesis.
• Pericytes regulate the blood-brain barrier and have been found to contain α-syn aggregates in PD brains.

Purpose of the Study:

• To investigate the role of pericytes in the clearance of pathological alpha-synuclein (α-syn) aggregates.
• To determine if pericytes can internalize and degrade different forms of fibrillar α-syn.
• To assess the potential of pericytes in reducing α-syn aggregate burden in the context of PD.

Main Methods:

• In vitro cell culture models (monoculture and mixed neuronal cultures) using pericytes.
• Treatment of pericytes with various fibrillar α-syn aggregate strains (Fibrils, Ribbons, fibrils65, fibrils91, fibrils110).
• Microscopic analysis to assess α-syn internalization and degradation by pericytes over time.

Main Results:

• Pericytes efficiently internalize various forms of fibrillar α-syn aggregates.
• Pericytes demonstrate the ability to cleave and degrade these α-syn aggregates.
• Degraded α-syn fragments remain within pericytes for up to 21 days, with aggregate size and cell count varying by strain initially.

Conclusions:

• Brain pericytes play a significant role in clearing α-syn aggregate burden.
• The brain vasculature, via pericytes, may represent a novel target for therapeutic intervention in Parkinson's disease.
• Understanding pericyte function in α-syn clearance could lead to strategies to slow PD progression.