Crosstalk between astrocytes and microglia results in increased degradation of α-synuclein and amyloid-β aggregates

Abstract

Background Alzheimer’s disease (AD) and Parkinson’s disease (PD) are characterized by brain accumulation of aggregated amyloid-beta (Aβ) and alpha-synuclein (αSYN), respectively. In order to develop effective therapies, it is crucial to understand how the Aβ/αSYN 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. Methods The aim of the present study was to investigate in which way glial crosstalk influences αSYN and Aβ pathology, focusing on accumulation and degradation. For this purpose, human-induced pluripotent cell (hiPSC)-derived astrocytes and microglia were exposed to sonicated fibrils of αSYN or Aβ 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. Results Our data show that intracellular deposits of αSYN and Aβ 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. Conclusions Taken together, our data demonstrate the importance of astrocyte and microglia interactions in Aβ/αSYN clearance, highlighting the relevance of glial cellular crosstalk in the progression of AD- and PD-related brain pathology.

Microglia jointly degrade fibrillar alpha-synuclein cargo by distribution through tunneling nanotubes

“…In addition to microglia, we found α-syn accumulations in cells negative for CD11b ( Figure 6 C, right side nucleus). Just recently, it has been described that microglia and astrocytes may interact in α-syn clearance, thereby exchanging α-syn among each other ( Rostami et al., 2021 ). Thus, it seems possible that microglia may transfer α-syn to other cell types, e.g., astrocytes, in our OSC experiments.…”

Cognitive enhancement and neuroprotective effects of OABL, a sesquiterpene lactone in 5xFAD Alzheimer's disease mice model

“…The microenvironment of early AD is characterized by inflammatory responses and oxidative stress, which precede the appearance of the amyloid cascade [ 7 ]. Inflammation is often accompanied by the activation of the immune system, which is ultimately mediated primarily by glial cells, such as microglia and astrocytes [ 58 , 59 ]. Among all non-neuronal CNS cells, microglia are thought to control the metabolic balance in the brain, including the secretion of pro-inflammatory or anti-inflammatory cytokines and phagocytosis of abnormal proteins [ 60 ].…”

Microglia and Astrocyte Function and Communication: What Do We Know in Humans?

“…To investigate the role of microglia/astrocyte communication in the clearance of protein deposition, human iPSC-derived microglia and astrocytes were co-cultured in the presence of Aβ or α-synuclein (αSYN) fibrils. Firstly, it was observed that microglia and astrocytes in co-culture had a greater ability to clear the protein aggregates compared to single-cell cultures, Rostami et al (2021) . This indicated synergy between the two cell types to provide a better mechanism of clearance.…”

“…This indicated synergy between the two cell types to provide a better mechanism of clearance. Moreover, live imaging analysis from the co-culture showed the appearance of novel physical structures called nanotubes (tunneling Structures made from cell membranes) keeping the astrocytes and microglia in direct contact for effective communication ( Rostami et al, 2021 ). A previous study conducted by the same group gave evidence that astrocytes were able to link via these structures to other astrocytes ( Rostami et al, 2017 ).…”