Dysfunction of autophagy and endosomal-lysosomal pathways: Roles in pathogenesis of Down syndrome and Alzheimer's Disease

Individuals with Down syndrome (DS) have an increased risk of early-onset Alzheimer's Disease (AD), largely owing to a triplication of the APP gene, located on chromosome 21. In DS and AD, defects in endocytosis and lysosomal function appear at the earliest stages of disease development and progress to widespread failure of intraneuronal waste clearance, neuritic dystrophy and neuronal cell death. The same genetic factors that cause or increase AD risk are also direct causes of endosomal-lysosomal dysfunction, underscoring the essential partnership between this dysfunction and APP metabolites in AD pathogenesis. The appearance of APP-dependent endosome anomalies in DS beginning in infancy and evolving into the full range of AD-related endosomal-lysosomal deficits provides a unique opportunity to characterize the earliest pathobiology of AD preceding the classical neuropathological hallmarks. Facilitating this characterization is the authentic recapitulation of this endosomal pathobiology in peripheral cells from people with DS and in trisomy mouse models. Here, we review current research on endocytic-lysosomal dysfunction in DS and AD, the emerging importance of APP/βCTF in initiating this dysfunction, and the potential roles of additional trisomy 21 genes in accelerating endosomal-lysosomal impairment in DS. Collectively, these studies underscore the growing value of investigating DS to probe the biological origins of AD as well as to understand and ameliorate the developmental disability of DS. [Display omitted] •APP-βCTF-mediated endo-lysosomal defects occur early in DS and AD.•Aberrant endosomal signaling contributes to cholinergic degeneration in DS and AD.•Altered endosomal trafficking leads to autophagic and neuritic defects in DS and AD.•Defects of lysosomal acidification and proteolysis are shared in DS and AD models.•Approaches are emerging to correct endo-lysosomal defects in DS and AD.