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HOPS disruption impairs APP trafficking and processing, promoting exosomal secretion of APP-CTFs
Derk Draper, Anna E. George, Tineke Veenendaal, Suzanne M. van Dijk, Elly Soltani, Paolo Sanzà, Frederik J. Verweij, Judith Klumperman et al.. Neurobiology of Disease, 2026-01-10
Topic: Brain proteins, microglia and lab models
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.
Key findings
- 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 den
Why it matters
This study shows that disruption of the HOPS complex impairs retromer-mediated recycling of APP, causing APP accumulation in late endosomes where BACE1 contributes to toxic APP C-terminal fragments, and enhances exosomal secretion of these fragments. The findings establish a mechanistic link between HOPS loss-of-function and aberrant APP processing, but they are laboratory results with implications for neurodegeneration rather than a demonstrated treatment.
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Study details
- Evidence strengthLow
How this study scored 39/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neurobiology of Disease) |
| Journal's citation record | 2 / 4 | Neurobiology of Disease: journal h-index 225 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 2 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 4 / 6 | Cited 8.3× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 2 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Ginny G. Farı́as: h-index 27 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Utrecht University: institution h-index 1,157 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41525887) |
| Free to read | 2 / 2 | Free to read |
| Total | 39 / 100 | — |
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Read the original
- DOI: 10.1016/j.nbd.2026.107269
- PubMed: 41525887
- Original source →
- Free full text: Neurobiology of Disease →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Draper, D., George, A. E., Veenendaal, T., van Dijk, S. M., Soltani, E., Sanzà, P., et al. (2026). HOPS disruption impairs APP trafficking and processing, promoting exosomal secretion of APP-CTFs. Neurobiology of Disease. https://doi.org/10.1016/j.nbd.2026.107269
Vancouver
Draper D, George AE, Veenendaal T, van Dijk SM, Soltani E, Sanzà P, et al. HOPS disruption impairs APP trafficking and processing, promoting exosomal secretion of APP-CTFs. Neurobiology of Disease. 2026. doi:10.1016/j.nbd.2026.107269. PMID: 41525887.
BibTeX
@article{draper2026-41525887,
author = {Draper, Derk and George, Anna E. and Veenendaal, Tineke and van Dijk, Suzanne M. and Soltani, Elly and Sanzà, Paolo and Verweij, Frederik J. and Klumperman, Judith and others},
title = {{HOPS disruption impairs APP trafficking and processing, promoting exosomal secretion of APP-CTFs}},
journal = {Neurobiology of Disease},
year = {2026},
doi = {10.1016/j.nbd.2026.107269},
pmid = {41525887},
url = {https://doi.org/10.1016/j.nbd.2026.107269}
}
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.