Extracellular vesicles study outlines new strategies to combat neurodegenerative diseases

A new study by the University of Barcelona could drive the design of future strategies to regenerate damaged brain areas in neurodegenerative diseases. The study emphasizes the role of neuron-derived extracellular vesicles in the processes that modulate synaptic plasticity and neuronal signalling pathways. In addition, the results outline a new scenario for using these extracellular vesicles derived from healthy neurons — capable of transporting molecules between cells — in treatments against neurodegenerative diseases.

Neuron-to-neuron communication

Neurons are capable of forming vesicles that transport molecules — proteins, lipids, RNA, etc. — to the outside, and regulate communication between nerve cells. These are extracellular vesicles, and even today there are still many unknowns about the role they play in communication between neurons in the nervous system.

The new study, performed with in vitro neuronal cultures from animal models, reveals that these vesicles are capable of transporting proteins — for example, PSD-95 and VGLUT-1 — and other determinants of communication processes between neurons.

“Although extracellular vesicles have been proposed as regulators of intercellular communication in the brain, most studies demonstrate this in models that are far from a physiological state and in vesicles whose origin is unknown. In this study we demonstrate that, in a physiological model without pathologies, neuron-specific extracellular vesicles regulate neuron-to-neuron communication and promote synaptic plasticity”, says Cristina Malagelada, professor at the UB Department of Biomedicine and researcher at the CIBERNED.

New strategies to combat neurodegeneration

Within the framework of the study, the team has applied complementary techniques to isolate the extracellular vesicles released by neurons, such as sequential ultracentrifugation or size exclusion chromatography. In addition, techniques have been used to characterize them, such as nanoparticle tracking analysis and transmission electron microscopy. These vesicles have also been used to perform treatments on healthy neurons and neurons deprived of nutrients.

Neuron-derived EVs reverse neuronal morphological alterations<
of neurons under nutrient-deprivation conditions

Cultured neurons were either cultured in Neurobasal complete medium (NCB) or deprived from B27 supplement for 24 h (ND-B27). Just after the deprivation, neurons were treated with EVs for 24 h, and neuron arborization and viability were analysed (A) Immunocytochemistry for MAP-2 (green) was performed to visualize cultured neurons and Hoechst 33342 (blue) was used to visualize nuclei. Using CellProfiler software, neurons and nuclei were classified as individual objects. Neuronal nuclei were selected and classified into viable or apoptotic. Neuron morphology was analysed using the MeasureObjectSkeleton module. (B) Neuron viability analysis. (C) Representative images of neuron morphology in untreated or EVs-treated neurons, either cultured in NBC or in NB-B27 conditions. Scale bar of 50 µm. (D) Schematic representation of the different types of branches in a neuron. Endpoints represent the number of branch termini and total length the length of all skeleton segments per object. (E) Morphological assessment of neuronal cultures. The number of primary dendrites, endpoints, and total tree length were analysed. Values represent culture replicates of four independent neuronal cultures (mean ± SEM). Data was analysed by two-way ANOVA (*P < 0.05 vs. NBC).

“Once neuron-neuron communication is understood in a non-pathological state, we want to address this question in the context of neurodegeneration. Therefore, it is crucial to be able to characterize the vesicles released by neurons in neurodegenerative diseases in order to understand the progression of these pathologies. In addition, we want to explore if, in a pathological model, we can reverse a more neurodegenerative trait with the treatment of extracellular vesicles derived from healthy neurons”, concludes the researcher.


Solana-Balaguer J, Campoy-Campos G, Martín-Flores N, Pérez-Sisqués L, Sitjà-Roqueta L, Kucukerden M, Gámez-Valero A, Coll-Manzano A, Martí E, Pérez-Navarro E, Alberch J, Soriano J, Masana M, Malagelada C. (2023) Neuron-derived extracellular vesicles contain synaptic proteins, promote spine formation, activate TrkB-mediated signalling and preserve neuronal complexity. J Extracell Vesicles 12(9):e12355. [article]

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