title: Autophagosomes cooperate in the degradation of intracellular C-terminal fragments of the amyloid precursor proteinviathe MVB/lysosomal pathway.
abstract: Brain regions affected by Alzheimer disease (AD) display well-recognized early neuropathologic features in the endolysosomal and autophagy systems of neurons, including enlargement of endosomal compartments, progressive accumulation of autophagic vacuoles, and lysosomal dysfunction. Although the primary causes of these disturbances are still under investigation, a growing body of evidence suggests that the amyloid precursor protein (APP) intracellular C-terminal fragment β (C99), generated by cleavage of APP by β-site APP cleaving enzyme 1 (BACE-1), is the primary cause of the endosome enlargement in AD and the earliest initiator of synaptic plasticity and long-term memory impairment. The aim of the present study was to evaluate the possible relationship between the endolysosomal degradation pathway and autophagy on the proteolytic processing and turnover of C99. We found that pharmacologic treatments that either inhibit autophagosome formation or block the fusion of autophagosomes to endolysosomal compartments caused an increase in C99 levels. We also found that inhibition of autophagosome formation by depletion of Atg5 led to higher levels of C99 and to its massive accumulation in the lumen of enlarged perinuclear, lysosomal-associated membrane protein 1 (LAMP1)-positive organelles. In contrast, activation of autophagosome formation, either by starvation or by inhibition of the mammalian target of rapamycin, enhanced lysosomal clearance of C99. Altogether, our results indicate that autophagosomes are key organelles to help avoid C99 accumulation preventing its deleterious effects.-González, A. E., Muñoz, V. C., Cavieres, V. A., Bustamante, H. A., Cornejo, V.-H., Januário, Y. C., González, I., Hetz, C., daSilva, L. L., Rojas-Fernández, A., Hay, R. T., Mardones, G. A., Burgos, P. V. Autophagosomes cooperate in the degradation of intracellular C-terminal fragments of the amyloid precursor proteinviathe MVB/lysosomal pathway.
authors.affiliation: Department of Physiology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Alexis E
authors.initials: AE
authors.lastname: González
authors.affiliation: Department of Physiology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Muñoz
authors.affiliation: Department of Physiology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Viviana A
authors.initials: VA
authors.lastname: Cavieres
authors.affiliation: Department of Physiology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Hianara A
authors.initials: HA
authors.lastname: Bustamante
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.|Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.
authors.forename: Víctor-Hugo
authors.initials: VH
authors.lastname: Cornejo
authors.affiliation: Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Yunan C
authors.initials: YC
authors.lastname: Januário
authors.affiliation: Department of Physiology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Ibeth
authors.initials: I
authors.lastname: González
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.|Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.|Buck Institute for Research on Aging, Novato, California, USA.|Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachussets, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
authors.affiliation: Department of Cell and Molecular Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil.
authors.forename: Luis L
authors.initials: LL
authors.lastname: daSilva
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, United Kingdom.|Center for Interdisciplinary Studies of the Nervous System (CISNe), Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Rojas-Fernández
authors.affiliation: Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Hay
authors.affiliation: Department of Physiology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile.|Center for Interdisciplinary Studies of the Nervous System (CISNe), Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Gonzalo A
authors.initials: GA
authors.lastname: Mardones
authors.affiliation: Department of Physiology, School of Medicine, Universidad Austral de Chile, Valdivia, Chile; patricia.burgos@uach.cl.|Center for Interdisciplinary Studies of the Nervous System (CISNe), Universidad Austral de Chile, Valdivia, Chile.
authors.forename: Patricia V
authors.initials: PV
authors.lastname: Burgos
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000071182:Autophagosomes / Q000502:physiology*; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D020868:Gene Silencing; D006801:Humans; D008247:Lysosomes / Q000502:physiology*; D057146:Multivesicular Bodies / Q000502:physiology*; D009287:Naphthyridines / Q000494:pharmacology; D009457:Neuroglia; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099177:Tsg101 Protein
chemical_list: D016564:Amyloid beta-Protein Precursor; D000071187:Autophagy-Related Protein 5; D004268:DNA-Binding Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D009287:Naphthyridines; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D000099177:Tsg101 Protein; C553294:1-(4-(4-propionylpiperazin-1-yl)-3-(trifluoromethyl)phenyl)-9-(quinolin-3-yl)benzo(h)(1,6)naphthyridin-2(1H)-one; C502778:ATG5 protein, human; C546842:MTOR protein, human
keywords: APP; Alzheimer disease; C99; amphisome; multivesicular bodies; proteostasis