Crosstalk Between Astrocytes And Microglia Results In Increased Degradation Of Alpha-Synuclein And Amyloid-Beta Aggregates

BackgroundAlzheimer's disease (AD) and Parkinson's disease (PD) are characterized by brain accumulation of aggregated amyloid-beta (A beta) and alpha-synuclein (alpha SYN), respectively. In order to develop effective therapies, it is crucial to understand how the A beta/alpha SYN aggregates can be cleared. Compelling data indicate that neuroinflammatory cells, including astrocytes and microglia, play a central role in the pathogenesis of AD and PD. However, how the interplay between the two cell types affects their clearing capacity and consequently the disease progression remains unclear.MethodsThe aim of the present study was to investigate in which way glial crosstalk influences alpha SYN and A beta pathology, focusing on accumulation and degradation. For this purpose, human-induced pluripotent cell (hiPSC)-derived astrocytes and microglia were exposed to sonicated fibrils of alpha SYN or A beta and analyzed over time. The capacity of the two cell types to clear extracellular and intracellular protein aggregates when either cultured separately or in co-culture was studied using immunocytochemistry and ELISA. Moreover, the capacity of cells to interact with and process protein aggregates was tracked using time-lapse microscopy and a customized "close-culture" chamber, in which the apical surfaces of astrocyte and microglia monocultures were separated by a <1 mm space.ResultsOur data show that intracellular deposits of SYN and A beta are significantly reduced in co-cultures of astrocytes and microglia, compared to monocultures of either cell type. Analysis of conditioned medium and imaging data from the "close-culture" chamber experiments indicate that astrocytes secrete a high proportion of their internalized protein aggregates, while microglia do not. Moreover, co-cultured astrocytes and microglia are in constant contact with each other via tunneling nanotubes and other membrane structures. Notably, our live cell imaging data demonstrate that microglia, when attached to the cell membrane of an astrocyte, can attract and clear intracellular protein deposits from the astrocyte.ConclusionsTaken together, our data demonstrate the importance of astrocyte and microglia interactions in A beta/alpha SYN clearance, highlighting the relevance of glial cellular crosstalk in the progression of AD- and PD-related brain pathology.