APP and β-amyloid modulate protein aggregation and dissociation from recycling endosomal and exosomal membranes

Singh, P. J.; Verma, B.; Wells, A.; Mendes, C. C.; Dunn, D.; Chen, Y.-N.; Oh, J.; Blincowe, L.; Wainwright, M.; Fischer, R.; Fan, S.-J.; Harris, A. L.; Goberdhan, D. C.; Wilson, C.

doi:10.1101/2024.03.28.586966

bioRxiv · 10.1101/2024.03.28.586966

APP and β-amyloid modulate protein aggregation and dissociation from recycling endosomal and exosomal membranes

Singh, P. J.·Verma, B.·Wells, A.·Mendes, C. C.·Dunn, D.·Chen, Y.-N.·Oh, J.·Blincowe, L.·Wainwright, M.·Fischer, R.·Fan, S.-J.·Harris, A. L.·Goberdhan, D. C.·Wilson, C.

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Abstract

Secretory proteins frequently aggregate into non-soluble dense-core granules (DCGs) in recycling endosome-like compartments prior to release. By contrast, aberrantly processed A{beta}-peptides derived from Amyloid Precursor Protein (APP) form pathological amyloidogenic aggregations in late-stage Alzheimers Disease (AD) after secretion. By examining living Drosophila prostate-like secondary cells, we show both APP and A{beta}-peptides affect normal DCG biogenesis. These cells generate DCGs and secreted nanovesicles called Rab11-exosomes within enlarged recycling endosomes. The fly APP homologue, APP-like (APPL), associates with Rab11-exosomes and the compartmental limiting membrane, from where its extracellular domain controls protein aggregation. Proteolytic release of this membrane-associated domain permits aggregates to coalesce into a large central DCG. Mutant A{beta}-peptide expression, like Appl loss-of-function, disrupts this assembly step and compartment motility, and increases lysosomal targeting, mirroring pathological events reported in early-stage AD. Our data therefore reveal a physiological role for APP in membrane-dependent protein aggregation, which when disrupted, rapidly triggers AD-relevant intracellular pathologies.

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Singh, P. J., Verma, B., Wells, A., Mendes, C. C., Dunn, D., Chen, Y.-N., Oh, J., Blincowe, L., Wainwright, M., Fischer, R., Fan, S.-J., Harris, A. L., Goberdhan, D. C., Wilson, C.. 2024-03-30. APP and β-amyloid modulate protein aggregation and dissociation from recycling endosomal and exosomal membranes. https://doi.org/10.1101/2024.03.28.586966

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