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Extracellular vesicles (EVs) are cell-derived membrane vesicles virtually secreted by all cells, including brain cells. EVs are a major term that includes apoptotic bodies, microvesicles and exosomes. The release of EVs has been recognized as an important modulator in cross-talking between neurons, astrocytes, microglia and oligodendrocytes, not only in central nervous system (CNS) physiology but also in neurodegenerative and neuroinflammatory disease states as well as in brain tumors, such as glioma. EVs are able to cross the blood brain barrier (BBB), spread to body fluids and reach distant tissues. This prominent spreading ability has suggested that EVs can be exploited into several different clinical applications ranging from biomarkers to therapeutic carriers. Exosomes, the well-studied group of EVs, have been emerging as a promising tool for therapeutic delivery strategies due to their intrinsic features, such as the stability, biocompatibility and stealth capacity when circulating in bloodstream, the ability to overcome natural barriers and inherent targeting properties. Over the last years, it became apparent that EVs can be loaded with specific cargoes directly in isolated EVs or by modulation of producer cells. In addition, the engineering of its membrane for targeting purposes is expected to allow generating carriers with unprecedented abilities for delivery in specific organs or tissues. Nevertheless, some challenges remain regarding the loading and targeting of EVs for which more research is necessary, and will be discussed in this review. Recently-emerged promising derivations are also discussed, such as exosome associated with adeno-associated virus (AAV) vectors (vexosomes), enveloped protein nanocages (EPNs) and exosome-mimetic nanovesicles. This article provides an updated review of this fast-progressing field of EVs and their role in brain diseases, particularly focusing in their therapeutic applications.

Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by an abnormal CAG expansion in the coding region of ATXN3/MJD1 gene. This confers a toxic gain-of-function to the ataxin-3 protein leading to neurodegeneration and severe motor impairments. There is no therapy to delay disease progression.MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at post-transcriptional level. miRNAs have been reported to play a significant role in a variety of diseases, including neurodegenerative disorders. However, the profiles and regulation of miRNAs in MJD are not well understood. Therefore, the aims of this study were 1) to screen the microRNA levels in a MJD mouse model and 2) to investigate functional effects of reestablishing normal levels of the de-regulated miRNAs using the same MJD mouse model.For this purpose, we used a MJD striatal lentiviral mouse model that we previously described (Simoes et al., 2012), by injecting mutant ataxin-3 in one hemisphere and wild type ataxin-3 (as an internal control) in the other hemisphere. Two weeks post-injection, miRNA expression was profiled by miRNA microarray analysis.Six miRNAs were found differentially expressed in MJD striatal samples, a result that was validated by qRT-PCR. We then used bioinformatic tools to predict the targets for the validated miRNAs and analyzed the respective levels. One candidate miR was up-regulated and the predicted target was down-regulated. To investigate whether reinstating the normal levels of the candidate miR would alleviate neuropathology, we then co-injected lentiviral vectors encoding an inhibitor of the candidate miR and mutant ataxin-3 in one hemisphere, and mutant ataxin-3 with miR negative inhibitor (as an internal control) in the other hemisphere. Five weeks post-injection we evaluated the neuropathological features and observed that in the hemisphere injected with the miR inhibitor there was a significant reduction of the loss of DARPP-32 neuronal marker and also a reduction of the mutant ataxin-3 aggregates as verified by western blot.Altogether our results provide new insights in the pathogenesis of MJD and identify a candidate miR that may be a promising target for MJD.