TY - JOUR
T1 - Changes in PGC‐1α/SIRT1 Signaling Impact on Mitochondrial Homeostasis in Amyloid-Beta Peptide Toxicity Model
AU - Panes, Jessica D.
AU - Godoy, Pamela A.
AU - Silva-Grecchi, Tiare
AU - Celis, María T.
AU - Ramirez-Molina, Oscar
AU - Gavilan, Javiera
AU - Muñoz-Montecino, Carola
AU - Castro, Patricio A.
AU - Moraga-Cid, Gustavo
AU - Yévenes, Gonzalo E.
AU - Guzmán, Leonardo
AU - Salisbury, Jeffrey L.
AU - Trushina, Eugenia
AU - Fuentealba, Jorge
N1 - Publisher Copyright:
© Copyright © 2020 Panes, Godoy, Silva-Grecchi, Celis, Ramirez-Molina, Gavilan, Muñoz-Montecino, Castro, Moraga-Cid, Yévenes, Guzmán, Salisbury, Trushina and Fuentealba.
PY - 2020/5/21
Y1 - 2020/5/21
N2 - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment that increasingly afflicts the elderly population. Soluble oligomers (AβOs) has been implicated in AD pathogenesis: however, the molecular events underlying a role for Aβ are not well understood. We studied the effects of AβOs on mitochondrial function and on key proteins that regulate mitochondrial dynamics and biogenesis in hippocampal neurons and PC-12 cells. We find that AβOs treatment caused a reduction in total Mfn1 after a 2 h exposure (42 ± 11%); while DRP1 increased at 1 and 2 h (205 ± 22% and 198 ± 27%, respectively), correlating to changes in mitochondrial morphology. We also observed that SIRT1 levels were reduced after acute and chronic AβOs treatment (68 ± 7% and 77 ± 6%, respectively); while PGC-1α levels were reduced with the same time treatments (68 ± 8% and 67 ± 7%, respectively). Interestingly, we found that chronic treatment with AβOs increased the levels of pSIRT1 (24 h: 157 ± 18%), and we observed changes in the PGC-1α and p-SIRT1 nucleus/cytosol ratio and SIRT1-PGC-1α interaction pattern after chronic exposure to AβOs. Our data suggest that AβOs induce important changes in the level and localization of mitochondrial proteins related with the loss of mitochondrial function that are mediated by a fast and sustained SIRT1/PGC-1α complex disruption promoting a “non-return point” to an irreversible synaptic failure and neuronal network disconnection.
AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment that increasingly afflicts the elderly population. Soluble oligomers (AβOs) has been implicated in AD pathogenesis: however, the molecular events underlying a role for Aβ are not well understood. We studied the effects of AβOs on mitochondrial function and on key proteins that regulate mitochondrial dynamics and biogenesis in hippocampal neurons and PC-12 cells. We find that AβOs treatment caused a reduction in total Mfn1 after a 2 h exposure (42 ± 11%); while DRP1 increased at 1 and 2 h (205 ± 22% and 198 ± 27%, respectively), correlating to changes in mitochondrial morphology. We also observed that SIRT1 levels were reduced after acute and chronic AβOs treatment (68 ± 7% and 77 ± 6%, respectively); while PGC-1α levels were reduced with the same time treatments (68 ± 8% and 67 ± 7%, respectively). Interestingly, we found that chronic treatment with AβOs increased the levels of pSIRT1 (24 h: 157 ± 18%), and we observed changes in the PGC-1α and p-SIRT1 nucleus/cytosol ratio and SIRT1-PGC-1α interaction pattern after chronic exposure to AβOs. Our data suggest that AβOs induce important changes in the level and localization of mitochondrial proteins related with the loss of mitochondrial function that are mediated by a fast and sustained SIRT1/PGC-1α complex disruption promoting a “non-return point” to an irreversible synaptic failure and neuronal network disconnection.
KW - Alzheimer's disease
KW - DRP1
KW - Mfn1
KW - PGC-1α
KW - SIRT1
KW - amyloid beta oligomers
KW - mitochondrial dysfunction
UR - http://www.scopus.com/inward/record.url?scp=85086223938&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85086223938&partnerID=8YFLogxK
U2 - 10.3389/fphar.2020.00709
DO - 10.3389/fphar.2020.00709
M3 - Article
AN - SCOPUS:85086223938
SN - 1663-9812
VL - 11
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 709
ER -