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

ABSTRACT: Secretory proteins frequently aggregate into non-soluble dense-core granules (DCGs) in recycling endosome-like compartments prior to release. By contrast, aberrantly processed Aβ-peptides derived from Amyloid Precursor Protein (APP) form pathological amyloidogenic aggregations in late-stage Alzheimer’s Disease (AD) after secretion. By examining living Drosophila prostate-like secondary cells, we show both APP and Aβ-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 these vesicles and the compartmental limiting membrane, from where its extracellular domain controls protein aggregation. Proteolytic release of this domain permits mini-aggregates to coalesce into a large central DCG. Mutant Aβ-peptide expression, like Appl loss-of-function, disrupts this assembly 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, triggers AD-relevant endolysosomal pathologies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Colon

DISEASE(S): Colon Cancer

SUBMITTER: Roman Fischer

LAB HEAD: Roman Fischer

PROVIDER: PXD053641 | Pride | 2025-07-10

REPOSITORIES: Pride

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			Action	DRS
	FL1183_MSQ1299_resubm_Shih-JungFan_TMT_F.msf	Msf
	FL1183_MSQ1299_resubm_Shih-JungFan_TMT_F1.raw	Raw
	FL1183_MSQ1299_resubm_Shih-JungFan_TMT_F2.raw	Raw
	FL1183_MSQ1299_resubm_Shih-JungFan_TMT_F3.raw	Raw
	FL1183_MSQ1299_resubm_Shih-JungFan_TMT_F4.raw	Raw

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