Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer’s Disease
Journal
Cells
ISSN
2073-4409
Date Issued
2022
Author(s)
Sandra Espinoza
Felipe Grunenwald
Wileidy Gomez
Felipe García
Sebastián Oyarce-Pezoa
Maria Fernanda Hernandez
Bastián I. Cortés
Daniela P. Ponce
Claudia Durán-Aniotz
Claudio Hetz
Carol D. SanMartín
Victor H. Cornejo
Valentina Parra
Patricio A. Manque
Diego Rojas-Rivera
René L. Vidal
Ute Woehlbier
Melissa Nassif
Type
Resource Types::text::journal::journal article
URL Institutional Repository
Abstract
<jats:p>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 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 therapeutically.</jats:p>
Cite this document
Espinoza, S., Grunenwald, F., Gomez, W., García, F., Abarzúa-Catalan, L., Oyarce-Pezoa, S., Hernandez, M. F., Cortés, B. I., Uhrig, M., Ponce, D. P., Durán-Aniotz, C., Hetz, C., SanMartín, C. D., Cornejo, V. H., Ezquer, F., Parra, V., Behrens, M. I., Manque, P. A., Rojas-Rivera, D., … Nassif, M. (2022). Neuronal rubicon represses extracellular app/amyloid β deposition in alzheimer’s disease. Cells, 11(12), 1860. https://doi.org/10.3390/cells11121860
Subjects
down-syndrome
;
a-beta
;
autophagy
;
protein
;
amygdala
;
neurodegeneration
;
dysregulation
;
accumulation
;
dysfunction
;
maturation
;
alzheimer disease
;
amyloid beta-peptides
;
amyloid beta-protein precursor
;
animals
;
humans
;
intracellular signaling peptides and proteins
;
mice
;
neuroblastoma
;
neurodegenerative diseases
;
neurons
;
amyloid beta protein
;
autophagy related protein 5
;
bafilomycin
;
beta actin
;
calcineurin
;
chloroquine
;
interleukin 6
;
neuronal rubicon
;
neurotrophic factor
;
octamer transcription factor 4
;
ras related protein rab 27a
;
sequestosome 1
;
transcription factor sox2
;
transforming growth factor beta
;
tumor necrosis factor
;
unclassified drug
;
amyloid beta protein
;
amyloid precursor protein
;
rubicon protein, mouse
;
signal peptide
;
alzheimer disease
;
amygdala
;
animal experiment
;
animal model
;
animal tissue
;
article
;
astrocytosis
;
autophagy (cellular)
;
autopsy
;
brain cortex
;
controlled study
;
dementia
;
densitometry
;
exosome
;
extracellular matrix
;
female
;
hippocampus
;
histology
;
homeostasis
;
human
;
human cell
;
human tissue
;
image analysis
;
immunocytochemistry
;
immunofluorescence
;
male
;
microglia
;
mouse
;
neuroblastoma cell
;
nonhuman
;
pluripotent stem cell
;
real time polymerase chain reaction
;
rna extraction
;
transgenic mouse
;
western blotting
;
animal
;
degenerative disease
;
metabolism
;
nerve cell
;
neuroblastoma