Abstract
In recent years, exploration of the brain extracellular space (ECS) has made remarkable progress, including nanoscopic characterizations. However, whether ECS precise conformation is altered during brain pathology remains unknown. Here we study the nanoscale organization of pathological ECS in adult mice under degenerative conditions. Using electron microscopy in cryofixed tissue and single nanotube tracking in live brain slices combined with super-resolution imaging analysis, we find enlarged ECS dimensions and increased nanoscale diffusion after α-synuclein-induced neurodegeneration. These animals display a degraded hyaluronan matrix in areas close to reactive microglia. Furthermore, experimental hyaluronan depletion in vivo reduces dopaminergic cell loss and α-synuclein load, induces microgliosis and increases ECS diffusivity, highlighting hyaluronan as diffusional barrier and local tissue organizer. These findings demonstrate the interplay of ECS, extracellular matrix and glia in pathology, unraveling ECS features relevant for the α-synuclein propagation hypothesis and suggesting matrix manipulation as a disease-modifying strategy.
Highlights
In recent years, exploration of the brain extracellular space (ECS) has made remarkable progress, including nanoscopic characterizations
Since volume fraction is a global parameter that takes into account the region sampled as a whole, to take advantage of the nanometric resolution achieved by Electron microscopy (EM) we explored local geometric variations by analyzing individual 2D compartments in binary images of the ECS (Fig. 1d)
Unravelling the ECS structure and function represents a technological challenge due to its nanometric dimensions, and despite recent remarkable advances[2,3,17,18,19], its precise morphological and diffusional parameters are still unknown in brain pathology
Summary
Unravelling the ECS structure and function represents a technological challenge due to its nanometric dimensions, and despite recent remarkable advances[2,3,17,18,19], its precise morphological and diffusional parameters are still unknown in brain pathology. We have demonstrated a link between ECS nanoscale parameters, ECM content and glia These mice display a degraded hyaluronan matrix in a context of reactive microglia, while experimental matrix disruption modified the pathology and increased ECS width and diffusion. The obvious hypothesis is that increased ECS diffusion might have a role in the spreading of toxic conformers of α-syn or other proteopathic seeds, and here we show that degrading hyaluronan in vivo (i.e. Hyase) reduces α-syn inoculum load This could be due to increased clearance of the inoculum through the ECS, reducing its chance to be internalized by cells, a quantitative model would better clarify this phenomenon. Studying local changes at the nanoscale, as opposed to global parameters spanning entire regions, is a paradigm shift in neurobiology that finds its latest bastion in the ECS This is the first study exploring ECS, ECM and glia in an integrative approach within a pathological context, and provides evidence of a dynamic interplay between these players. The possibility to combine nanoscale ECS exploration with ECM, cellular and subcellular labeling will open new avenues to further understand brain physiology in health and disease
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