HOPS disruption impairs APP trafficking and processing, promoting exosomal secretion of APP-CTFs

Amyloid precursor protein (APP) is a key player in various neuronal functions but also the source for toxic Aβ that accumulates in the brain of Alzheimer patients. APP trafficking and processing depend on the endo -lysosomal system, but the molecular mechanisms that coordinate these processes remain not fully understood. Here, we studied the HOPS complex, a central regulator of endo-lysosomal maturation. We show that HOPS disruption impairs retromer-mediated recycling of APP to the TGN, resulting in the accumulation of APP in late endosomes. In neurons, this accumulation is spatially restricted to somatodendritic endosomes. These APP-containing endosomes are catalytically inactive and lack the γ-secretase subunit PSEN2. However, they do contain BACE1, which contributes to the build-up of toxic APP C-terminal fragments (APP-CTFs). Notably, loss of HOPS function enhances secretion of APP-CTFs by exosomes, suggesting a potential mechanism for disease propagation. Together, our findings establish a mechanistic link between HOPS loss-of-function and aberrant APP processing, with implications for neurodegeneration. • HOPS impairment blocks retromer-mediated recycling of APP to the TGN. • HOPS impairment redistributes APP to static late endosomes in soma and dendrites. • HOPS impairment increases APP and BACE1 colocalization, promoting APP-CTF formation. • APP-CTF positive late endosomes are catalytically inactive and lack PSEN2. • HOPS impaired cells secrete APP-CTFs by EVs, potentially promoting disease spread.