AP2S1 regulates APP degradation through late endosome–lysosome fusion in cells and APP/PS1 mice

AP2S1 is the sigma 2 subunit of adaptor protein 2 (AP2) that is essential for endocytosis. In this study, we investigated the potential role of AP2S1 in intracellular processing of amyloid precursor protein (APP), which contributes to the pathogenesis of Alzheimer disease (AD) by generating the toxic β‐amyloid peptide (Aβ). We found that knockdown or overexpression of AP2S1 decreased or increased the protein levels of APP and Aβ in cells stably expressing human full‐length APP695, respectively. This effect was unrelated to endocytosis but involved lysosomal degradation. Morphological studies revealed that silencing of AP2S1 promoted the translocalization of APP from RAB9‐positive late endosomes (LE) to LAMP1‐positive lysosomes, which was paralleled by the enhanced LE‐lysosome fusion. In support, silencing of vacuolar protein sorting‐associated protein 41 (VPS41) that is implicated in LE‐lyso fusion prevented AP2S1‐mediated regulation of APP degradation and translocalization. In APP/PS1 mice, an animal model of AD, AAV‐mediated delivery of AP2S1 shRNA in the hippocampus significantly reduced the protein levels of APP and Aβ, with the concomitant APP translocalization, LE‐lyso fusion and the improved cognitive functions. Taken together, these data uncover a LE‐lyso fusion mechanism in APP degradation and suggest a novel role for AP2S1 in the pathophysiology of AD.