Focusing on cellular biomarkers: The endo-lysosomal pathway in Down syndrome.

Down syndrome (DS) is the most frequent chromosomal disorder. It is caused by the triplication of human chromosome 21, leading to increased dosage of a variety of genes including APP (Amyloid Precursor Protein). Mainly for this reason, individuals with DS are at high risk to develop Alzheimer's disease (AD). Extensive literature identified various morphological and molecular abnormalities in the endo-lysosomal pathway both in DS and AD. Most studies in this field investigated the causative role of APP (Amyloid Precursor Protein) in endo-lysosomal dysfunctions, thus linking phenotypes observed in DS and AD. In DS context, several lines of evidence and emerging hypotheses suggest that other molecular players and pathways may be implicated in these complex phenotypes. In this review, we outline the normal functioning of endosomal trafficking and summarize the research on endo-lysosomal dysfunction in DS in light of AD findings. We emphasize the role of genes of chromosome 21 implicated in endocytosis to explain endosomal abnormalities and set the limitations and perspectives of models used to explore endo-lysosomal dysfunction in DS and find new biomarkers. The review highlights the complexity of endo-lysosomal dysfunction in DS and suggests directions for future research in the field.