Traffic (Copenhagen, Denmark), 2023-01, Vol.24 (1), p.20-33
2023
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- Autor(en) / Beteiligte
- Titel
- AP2S1 regulates APP degradation through late endosome–lysosome fusion in cells and APP/PS1 mice
- Ist Teil von
- Traffic (Copenhagen, Denmark), 2023-01, Vol.24 (1), p.20-33
- Ort / Verlag
- Former Munksgaard: John Wiley & Sons A/S
- Erscheinungsjahr
- 2023
- Quelle
- Wiley Online Library - AutoHoldings Journals
- Beschreibungen/Notizen
- AP2S1 is the sigma 2 subunit of adaptor protein 2 (AP2) that is essential for endocytosis. In this study, we investigated the potential role of AP2S1 in intracellular processing of amyloid precursor protein (APP), which contributes to the pathogenesis of Alzheimer disease (AD) by generating the toxic β‐amyloid peptide (Aβ). We found that knockdown or overexpression of AP2S1 decreased or increased the protein levels of APP and Aβ in cells stably expressing human full‐length APP695, respectively. This effect was unrelated to endocytosis but involved lysosomal degradation. Morphological studies revealed that silencing of AP2S1 promoted the translocalization of APP from RAB9‐positive late endosomes (LE) to LAMP1‐positive lysosomes, which was paralleled by the enhanced LE‐lysosome fusion. In support, silencing of vacuolar protein sorting‐associated protein 41 (VPS41) that is implicated in LE‐lyso fusion prevented AP2S1‐mediated regulation of APP degradation and translocalization. In APP/PS1 mice, an animal model of AD, AAV‐mediated delivery of AP2S1 shRNA in the hippocampus significantly reduced the protein levels of APP and Aβ, with the concomitant APP translocalization, LE‐lyso fusion and the improved cognitive functions. Taken together, these data uncover a LE‐lyso fusion mechanism in APP degradation and suggest a novel role for AP2S1 in the pathophysiology of AD. Fission events at endo‐lyso interface could be favored in the presence of AP2S1, which is reminiscent of membrane fission during endocytosis. In contrast, lack of AP2S1 may inhibit this process, and alternatively facilitate endo‐lyso fusion and content exchange, leading to lysosomal degradation of APP.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1398-9219eISSN: 1600-0854DOI: 10.1111/tra.12874Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_10107530
- Format
- –
- Schlagworte
- Adapter protein 2, Adaptor Protein Complex 2 - metabolism, Adaptor Protein Complex sigma Subunits - metabolism, Alzheimer disease, Alzheimer Disease - metabolism, Alzheimer's disease, Amyloid beta-Peptides - metabolism, Amyloid beta-Protein Precursor - genetics, Amyloid beta-Protein Precursor - metabolism, Amyloid precursor protein, Amyloid Precursor Protein Secretases - metabolism, Animal models, Animals, APP, Cell fusion, Cognitive ability, Degradation, Endocytosis, Endosomes, Endosomes - metabolism, Endosome–lysosome fusion, Humans, Lysosomes, Lysosomes - metabolism, Mice, Neurodegenerative diseases, Presenilin 1, Protein transport, Proteins, rab GTP-Binding Proteins - metabolism, Sigma subunit, β-Amyloid