Exosomes are small extracellular vesicles released by almost all cell types in physiological and pathological conditions. The exosomal potential to unravel disease mechanisms, or to be used as a source of biomarkers, is being explored, in particularly in the field of neurodegenerative diseases. Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the world and exosomes appear to have a relevant role in disease pathogenesis. This review summarizes the current knowledge on exosome contributions to AD as well as their use as disease biomarker resources or therapeutic targets. The most recent findings with respect to both protein and miRNA biomarker candidates for AD, herein described, highlight the state of the art in this field and encourage the use of exosomes derived from biofluids in clinical practice in the near future.

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The potential of exosomes as biomarker resources for diagnostics and even for therapeutics has intensified research in the field, including in the context of Alzheimer´s disease (AD). The search for disease biomarkers in peripheral biofluids is advancing mainly due to the easy access it offers. In the study presented here, emphasis was given to the bioinformatic identification of putative exosomal candidates for AD. The exosomal proteomes of cerebrospinal fluid (CSF), serum and plasma, were obtained from three databases (ExoCarta, EVpedia and Vesiclepedia), and complemented with additional exosomal proteins already associated with AD but not found in the databases. The final biofluids’ proteomes were submitted to gene ontology (GO) enrichment analysis and the exosomal Aβ-binding proteins that can constitute putative candidates were identified. Among these candidates, gelsolin, a protein known to be involved in inhibiting Abeta fibril formation, was identified, and it was tested in human samples. The levels of this Aβ-binding protein, with anti-amyloidogenic properties, were assessed in serum-derived exosomes isolated from controls and individuals with dementia, including AD cases, and revealed altered expression patterns. Identification of potential peripheral biomarker candidates for AD may be useful, not only for early disease diagnosis but also in drug trials and to monitor disease progression, allowing for a timely therapeutic intervention, which will positively impact the patient’s quality of life.

Extracellular vesicles (EVs) are gaining increased importance in fundamental research as key players in disease pathogenic mechanisms, but also in translational and clinical research due to their value in biomarker discovery, either for diagnostics and/or therapeutics. In the first research scenario, the study of EVs isolated from neuronal models mimicking neurodegenerative diseases can open new avenues to better understand the pathological mechanisms underlying these conditions or to identify novel molecular targets for diagnosis and/or therapeutics. In the second research scenario, the easy availability of EVs in body fluids and the specificity of their cargo, which can reflect the cell of origin or disease profiles, turn these into attractive diagnostic tools. EVs with exosome‐like characteristics, circulating in the bloodstream and other peripheral biofluids, constitute a non‐invasive and rapid alternative to study several conditions, including brain‐related disorders. In both cases, several EVs isolation methods are already available, but each neuronal model or biofluid presents its own challenges. Herein, a literature overview on EVs isolation methodologies from distinct neuronal models (cellular culture and brain tissue) and body fluids (serum, plasma, cerebrospinal fluid, urine and saliva) was carried out. Focus was given to approaches employed in the context of Alzheimer's and Parkinson's diseases, and the main research findings discussed. The topics here revised will facilitate the choice of EVs isolation methodologies and potentially prompt new discoveries in EVs research and in the neurodegenerative diseases field.

Background: Chronic inflammation is a feature of Alzheimer´s disease (AD), resulting in excessive production of inflammatory mediators that can lead to neuroinflammation, contributing to alterations in Ab production and deposition as Senile Plaques (SPs), and to neurofibrillary tangles (NFTs) formation, due to hyperphosphorylated Tau protein. Objective: This work addressed the impact of the interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), two chemokines, on Tau phosphorylation; also evaluated the chemokines’ levels in plasma using samples from a regional cohort. Method: Human neuronal SH-SY5Y cells exposed to IL-8 and MCP-1 chemokines were monitored for their protein and phosphorylated protein levels by western blotting analysis. A serine/threonine protein phosphatase (PPs) activity assay was employed to monitor PPs activity. Subsequently, flow cytometry was used to monitor chemokines levels in plasma samples from individuals with cognitive deficits. Results: Chemokines’ exposure resulted only in minor cytotoxicity effects on SH-SY5Y, and in increased Tau phosphorylation, particularly at the S396 residue. Tau phosphorylation correlated with PPs inhibition and was consistent with GSK3b phosphorylation-mediated inhibition. Subsequent analysis of plasma from individuals with cognitive deficits showed that IL-8 levels were decreased. Conclusion: Data shows that both chemokines tested can exert an effect on GSK3b phosphorylation and modulate PPs activity, potentially resulting in increased Tau phosphorylation and subsequent NFTs formation. One can deduce that increased chemokines stimulation during chronic inflammation can exacerbate this event. The work contributes to a better understanding of the mode of action of these chemokines on AD pathogenesis and opens novel research avenues.