Neuronal rubicon represses extracellular APP/amyloid beta deposition in Alzheimer's disease
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2022Metadata
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Espinoza, Sandra
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Neuronal rubicon represses extracellular APP/amyloid beta deposition in Alzheimer's disease
Author
- Espinoza, Sandra;
- Grunenwald, Felipe;
- Gomez, Wileidy;
- García, Felipe;
- Abarzúa Catalán, Lorena;
- Oyarce Pezoa, Sebastián;
- Hernández, María Fernanda;
- Cortés, Bastián I.;
- Uhrig, Markus;
- Ponce de la Vega, Daniela Paz;
- Durán Aniotz, Claudia;
- Hetz Flores, Claudio Andres;
- San Martín Rovirosa, Carol Dazil;
- Cornejo Corona, Víctor Hugo;
- Ezquer, Fernando;
- Parra Ortiz, Valentina María;
- Behrens Pellegrino, María Isabel Ofelia;
- Manque, Patricio A.;
- Rojas Rivera, Diego;
- Vidal, René L.;
- Woehlbier, Ute;
- Nassif, Melissa;
Abstract
Alzheimer's disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells. However, Rubicon participates in different pathways depending on cell type, and little information is currently available on neuronal Rubicon's role in the AD context. Here, we investigated the cell-specific expression of Rubicon in postmortem brain samples from AD patients and 5xFAD mice and its impact on amyloid beta burden in vivo and neuroblastoma cells. Further, we assessed Rubicon levels in human-induced pluripotent stem cells (hiPSCs), derived from early-to-moderate AD and in postmortem samples from severe AD patients. We found increased Rubicon levels in AD-hiPSCs and postmortem samples and a notable Rubicon localization in neurons. In AD transgenic mice lacking Rubicon, we observed intensified amyloid beta burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APP/amyloid beta secretion in the medium was found when Rubicon was absent, which was not observed in cells depleted of Atg5, essential for autophagy, or Rab27a, required for exosome secretion. Our results propose an uncharacterized role of Rubicon on APP/amyloid beta homeostasis, in which neuronal Rubicon is a repressor of APP/amyloid beta secretion, defining a new way to target AD and other similar diseases therapeutically.
Patrocinador
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
CONICYT FONDECYT 11160288
1200459
1191003
11180546
11171061
1190958
1200287
1190743
FONDAP 15130011
U-Redes Generacion, Vicerrectoria de Investigacion y Desarrollo, Universidad de Chile URG-035/1
CRP-ICGEB CHL18-04
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Artículo de publícación WoS
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Cells 2022, 11, 1860
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