Targeting RPSA to modulate endosomal trafficking and amyloidogenesis in genetic Alzheimer's disease

: The "amyloid cascade hypothesis" for Alzheimer's disease (AD) pathogenesis, highlights the accumulation of amyloid-β (Aβ) as a crucial trigger for the pathology. However, AD is an extremely complex disease influenced by multiple pathophysiological processes, making it impossible to attribute its onset to a single hypothesis. The endocytic pathway, where the amyloidogenic processing of APP occurs, has emerged as a pathogenic "hub" for AD. In this study, we found altered homeostasis and dynamics of endolysosomal compartments in fibroblasts from patients affected by a genetic form of AD (APP V717I mutation). These alterations corresponded to an abnormal trafficking of APP along the endolysosomal pathway, favouring its amyloidogenic processing. The identification of APP interactors involved in its trafficking and processing, and finding molecules able to interfere with these interactions, represents a promising therapeutic approach. However, the role of endosomal pathway and the possibility of modulating APP processing through it remains elusive. Among the proteins participating to APP metabolism, the RPSA receptor and its inhibitor molecule NSC47924 have been identified. In this study, we found that the inhibitor, likely by displacing APP from interaction with its receptor, reduced APP accumulation in EEs in AD cells, finally restoring both endosomal dynamics and APP distribution to those of unaffected cells. We also demonstrated that RPSA inhibition affected the aberrant APP cleavage, as it reduced the production of both APP-βCTF (C-Terminal Fragment) and Aβ in AD fibroblasts. These results highlight significant differences in endolysosomal compartments and APP processing in AD-affected cells, refining our understanding of APP/RPSA intersection.