Espinoza, SandraGrunenwald, FelipeGomez, WileidyGarcía, FelipeAbarzúa, LorenaOyarce, SebastiánHernández, MaríaCortés, BastiánUhrig, MarkusPonce, DanielaDurán, ClaudiaHetz, ClaudioSanMartín, CarolCornejo, VictorEzquer, FernandoParra, ValentinaBehrens, MaríaManque, PatricioRojas, DiegoVidal, RenéWoehlbier, UteNassif, Melissa2022-11-142022-11-142022Espinoza, S.; Grunenwald, F.; Gomez, W.; García, F.; Abarzúa-Catalan, L.; Oyarce-Pezoa, S.; Hernandez, M.F.; Cortés, B.I.; Uhrig, M.; Ponce, D.P.; et al. Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer’s Disease. Cells 2022, 11, 1860. https:// doi.org/10.3390/cells11121860https://doi.org/10.3390/cells11121860http://hdl.handle.net/11447/6657Alzheimer’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 β 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 β burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APP/amyloid β 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 β homeostasis, in which neuronal Rubicon is a repressor of APP/amyloid β secretion, defining a new way to target AD and other similar diseases therapeuticallyenAlzheimer’s diseaseAutophagyRubiconKIAA0226RUBCNAPPKIAA0226LPacerArticle