Objective: To explore the brain extracellular space and its matrix at a nanometric scale in a context of α-synuclein-induced neurodegeneration.

Background: The extracellular space (ECS) is a system of interconnected compartments constituted by a dynamic scaffold known as the extracellular matrix (ECM). In the brain, the ECS plays a key role in intercellular communication and spreading and clearance of disease-related molecules. In pathological conditions, the ECS volume is affected in response to inflammation and tissue remodeling after neuronal death and glial cell adaptations. Changes in the highly-hygroscopic hyaluronan (HA) network can dramatically modify the ECS volume. Lewy Bodies (LB), the hallmark of Parkinson’s disease, are intraneuronal proteinaceous inclusions mainly constituted by misfolded species of α-synuclein. The ECS/ECM participate both in the spreading of toxic conformers of α-synuclein and in the regulation of inflammation, key events leading to the loss of dopaminergic neurons in the substantia nigra (SN).

Methods: We sought to explore the ECS/ECM changes in LB-injected mice, a unique parkinsonian model where LB fractions isolated from PD patients are inoculated in the SN, inducing a progressive PD-like neurodegeneration in the substantia nigra. High-pressure cryo-fixation of ventral midbrain acute slices and electron microscopy provided data about the ECS volume. ECS local viscosity was assessed by single-molecule tracking of single-walled carbon nanotubes (SWCNTs) by near-infrared microscopy. Finally, the hyaluronan matrix and microglial cells were analyzed by immunofluorescence.

Results: We detected a local ECS disorganization at nanoscale level in LB-injected mice. Pockets of increased local thickness, as well as decreased local viscosity were identified into the SN by Cryo-EM and SWCNTs tracking. We observed a substantial decrease of the HA network in LB-injected mice compared to controls, and engulfment of HA structures by activated microglia.

Conclusions: These results reveal a disorganization of the extracellular space in the SN of parkinsonian mice, as a result of decreased levels of hyaluronan and microglial activation. Our results provide insight on a crucial and underexplored component of the brain and adds to our understanding of the pathophysiology of PD.

References: A. Recasens, B. Dehay, J. Bove, I. Carballo-Carbajal, S. Dovero, A. Perez-Villalba, P.O. Fernagut, J. Blesa, A. Parent, C. Perier, I. Farinas, J.A. Obeso, E. Bezard, M. Vila, Lewy body extracts from Parkinson disease brains trigger alpha-synuclein pathology and neurodegeneration in mice and monkeys, Ann Neurol, 75 (2014) 351-362.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/nanoscale-imaging-reveals-disorganization-of-the-brain-extracellular-space-in-lewy-body-injected-mice/