Singh, Preman J;
Verma, Bhavna;
Wells, Adam;
Mendes, Cláudia C;
Dunn, Dali;
Chen, Ying-Ni;
Oh, Jade;
... Wilson, Clive; + view all
(2025)
Amyloid-β disrupts APP-regulated protein aggregation and dissociation from recycling endosomal membranes.
The EMBO Journal
, 44
(16)
pp. 4443-4472.
10.1038/s44318-025-00497-y.
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Abstract
Secretory proteins aggregate into non-soluble dense-core granules in recycling endosome-like compartments prior to regulated release. By contrast, aberrantly processed, secreted amyloid-β (Aβ) peptides derived from amyloid precursor protein (APP) form pathological extracellular amyloidogenic aggregations in late-stage Alzheimer’s disease (AD). By examining living Drosophila prostate-like secondary cells, we show that both APP and Aβ peptides affect normal biogenesis of dense-core granules. These cells generate dense-core granules and secreted nanovesicles called Rab11-exosomes via evolutionarily conserved mechanisms within highly enlarged secretory compartments with recycling endosomal identity. The fly APP homologue, APP-like (APPL), associates with these vesicles and the compartmental limiting membrane, from where its extracellular domain modulates protein aggregation. Proteolytic release of this domain permits mini-aggregates to coalesce into a large central dense-core granule. Mutant Aβ expression disrupts this process and compartment motility, and increases aberrant lysosomal targeting, mirroring previously unexplained early-stage pathological events in AD. It also promotes cell-to-cell propagation of these endolysosomal defects, again phenocopying changes observed in AD. Our data therefore demonstrate physiological roles for APP in membrane-dependent protein aggregation, involving molecular mechanisms, which when disrupted by Aβ peptides, trigger Alzheimer’s disease-relevant pathologies.
| Type: | Article |
|---|---|
| Title: | Amyloid-β disrupts APP-regulated protein aggregation and dissociation from recycling endosomal membranes |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s44318-025-00497-y |
| Publisher version: | https://doi.org/10.1038/s44318-025-00497-y |
| Language: | English |
| Additional information: | © 2025 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10217306 |
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