PloS one, 2010-06, Vol.5 (6), p.e11102-e11102
2010
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Regulation of amyloid precursor protein processing by the Beclin 1 complex
- Ist Teil von
- PloS one, 2010-06, Vol.5 (6), p.e11102-e11102
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2010
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Autophagy is an intracellular degradation pathway that functions in protein and organelle turnover in response to starvation and cellular stress. Autophagy is initiated by the formation of a complex containing Beclin 1 (BECN1) and its binding partner Phosphoinositide-3-kinase, class 3 (PIK3C3). Recently, BECN1 deficiency was shown to enhance the pathology of a mouse model of Alzheimer Disease (AD). However, the mechanism by which BECN1 or autophagy mediate these effects are unknown. Here, we report that the levels of Amyloid precursor protein (APP) and its metabolites can be reduced through autophagy activation, indicating that they are a substrate for autophagy. Furthermore, we find that knockdown of Becn1 in cell culture increases the levels of APP and its metabolites. Accumulation of APP and APP C-terminal fragments (APP-CTF) are accompanied by impaired autophagosomal clearance. Pharmacological inhibition of autophagosomal-lysosomal degradation causes a comparable accumulation of APP and APP-metabolites in autophagosomes. Becn1 reduction in cell culture leads to lower levels of its binding partner Pik3c3 and increased presence of Microtubule-associated protein 1, light chain 3 (LC3). Overexpression of Becn1, on the other hand, reduces cellular APP levels. In line with these observations, we detected less BECN1 and PIK3C3 but more LC3 protein in brains of AD patients. We conclude that BECN1 regulates APP processing and turnover. BECN1 is involved in autophagy initiation and autophagosome clearance. Accordingly, BECN1 deficiency disrupts cellular autophagy and autophagosomal-lysosomal degradation and alters APP metabolism. Together, our findings suggest that autophagy and the BECN1-PIK3C3 complex regulate APP processing and play an important role in AD pathology.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0011102Titel-ID: cdi_plos_journals_1292420071
- Format
- –
- Schlagworte
- Accumulation, Advertising executives, Alzheimer Disease - metabolism, Alzheimer's disease, Amyloid beta-protein, Amyloid beta-Protein Precursor - metabolism, Amyloid precursor protein, Apoptosis, Apoptosis Regulatory Proteins - genetics, Apoptosis Regulatory Proteins - physiology, Autophagy, Beclin-1, Binding, Biochemistry/Cell Signaling and Trafficking Structures, Biochemistry/Protein Folding, Brain research, Cell Biology/Cellular Death and Stress Responses, Cell culture, Cell death, Cellular stress response, Degradation, Extracellular matrix, Gene Knockdown Techniques, Humans, Hydrolysis, Kinases, Localization, Lysosomes, Medicine, Membrane Proteins - genetics, Membrane Proteins - physiology, Metabolism, Metabolites, Microscopy, Microtubule-associated protein 1, Mutation, Neurodegeneration, Neurodegenerative diseases, Neurological Disorders/Alzheimer Disease, Neurology, Neuroscience/Neurobiology of Disease and Regeneration, Pathology, Phagocytosis, Phagosomes, Pharmacology, Phosphatidylinositol 3-Kinases - metabolism, Physiological aspects, Precursors, Protein Processing, Post-Translational, Protein turnover, Proteins, Rodents, Transgenic animals, β-Amyloid