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.

Aging is the main risk factor for the appearance of age-related neurodegenerative diseases, including Alzheimer's disease (AD). AD is the most common form of dementia, characterized by the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), the main histopathological hallmarks in AD brains. The core of these deposits are predominantly amyloid fibrils in SPs and hyperphosphorylated Tau protein in NFTs, but other molecular components can be found associated with these pathological lesions. Herein, an extensive literature review was carried out to obtain the SPs and NFTs proteomes, followed by a bioinformatic analysis and further putative biomarker validation. For SPs, 857 proteins were recovered, and, for NFTs, 627 proteins of which 375 occur in both groups and represent the common proteome. Gene Ontology (GO) enrichment analysis permitted the identification of biological processes and the molecular functions most associated with these lesions. Analysis of the SPs and NFTs common proteins unraveled pathways and molecular targets linking both histopathological events. Further, validation of a putative phosphotarget arising from the in silico analysis was performed in serum-derived extracellular vesicles from AD patients. This bioinformatic approach contributed to the identification of putative molecular targets, valuable for AD diagnostic or therapeutic intervention.

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Background Senile plaques (SPs) and neurofibrillary tangles (NFTs) are the main histopathological hallmarks of Alzheimer’s disease (AD). Although these two deposits have main components, like amyloid fibrils in SPs and hyperphosphorylated tau protein in NFTs, the molecular composition underlying these lesions has not been completely unraveled. Hence, this work aims to characterize the SPs and NFTs proteomes’ by applying a bioinformatic analysis, to identify new possible biomarkers candidates for AD. Method An extensive literature research was carried out on Pubmed, using keywords that allowed the recovery of information regarding SPs and NFTs proteomes in AD brains. The data obtained was loaded and analysed on Cytoscape v3.8.2. For the Gene Ontology (GO) analysis, the plugins ClueGO v2.5.8 + CluePedia v1.5.8 were employed. Result More than 800 proteins were identified for SPs and more than 600 for the NFTs. GO analyses allowed the characterization of both proteomes at the biological process, molecular function, and cellular component levels. The top biological processes for SPs were related to cell development, secretion, and exocytosis, while for NFTs these were related to protein localization, vesicle‐mediated transport in synapse, and response to oxidative stress. Overlap of both proteomes revealed more than 300 proteins that represent interesting targets for AD. GO analyses revealed that these proteins are involved in biological processes like vesicle‐mediated transport in synapse and apoptotic signaling pathway. Additional experiments using antibody‐based methodologies need to be carried out to validate the potential of these candidates for AD. Conclusion This study allowed the identification of several proteins, present in both SPs and NFTs, that can not only assist in unraveling pathways common to both histopathological hallmarks but also constitute possible biomarker candidates for AD diagnosis and/or therapeutics. To this end research was funded by a grant from the Alzheimer’s Association (2019‐AARG‐644347) and supported by iBiMED UIDB/04501/2020, FCT, COMPETE program, QREN, European Union. T.S.M. is supported by the FCT through the individual PhD grant (SFRH/BD/145979/2019). RV’s Fellowship Grant (IF/00286/2015).