| Title: |
HOPS disruption impairs APP trafficking and processing, promoting exosomal secretion of APP-CTFs |
| Authors: |
Draper, Derk; George,Anna E; Veenendaal, Tineke; van Dijk,Suzanne; Soltani, Elly; Sanzà,Paolo; Verweij,Frederik J; Klumperman, Judith; Farías,Ginny G; CMM Groep Klumperman; Cancer; CMM groep Liv; Brain; CMM Sectie Celbiologie; Regenerative Medicine and Stem Cells |
| Publication Year: |
2026 |
| Subject Terms: |
Journal Article |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
0969-9961 |
| Relation: |
https://dspace.library.uu.nl/handle/1874/469175 |
| Availability: |
https://dspace.library.uu.nl/handle/1874/469175 |
| Rights: |
info:eu-repo/semantics/OpenAccess |
| Accession Number: |
edsbas.F5E8DE37 |
| Database: |
BASE |