Changes in PGC‐1α/SIRT1 Signaling Impact on Mitochondrial Homeostasis in Amyloid-Beta Peptide Toxicity Model

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment that increasingly afflicts the elderly population. Soluble oligomers (AbOs) has been implicated in AD pathogenesis: however, the molecular events underlying a role for Ab are not well understood. We studied the effects of AbOs on mitochondrial function and on key proteins that regulate mitochondrial dynamics and biogenesis in hippocampal neurons and PC-12 cells. We find that AbOs 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 AbOs treatment (68 ± 7% and 77 ± 6%, respectively); while PGC-1a levels were reduced with the same time treatments (68 ± 8% and 67 ± 7%, respectively). Interestingly, we found that chronic treatment with AbOs increased the levels of pSIRT1 (24 h: 157 ± 18%), and we observed changes in the PGC-1a and p-SIRT1 nucleus/cytosol ratio and SIRT1-PGC-1a interaction pattern after chronic exposure to AbOs. Our data suggest that AbOs 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-1a complex disruption promoting a "non-return point" to an irreversible synaptic failure and neuronal network disconnection.

Physical Exercise and Alzheimer’s Disease: Effects on Pathophysiological Molecular Pathways of the Disease

“…Thus, a reduced expression of PGC-1α in the hippocampus is correlated with the progression of amyloid neuropathy in AD patients [ 124 ]. Panes et al considered that PGC-1α “sequestered” in the cytosol could be the non-return point for the neuron on the Aβ toxicity [ 125 ]. Low levels of PGC-1α are also associated with abnormal brain insulin signaling [ 126 ].…”

Blood–Brain Barrier and Neurovascular Unit In Vitro Models for Studying Mitochondria-Driven Molecular Mechanisms of Neurodegeneration

“…However, in Alzheimer’s disease, mitochondrial mass is reduced due to impaired mitochondrial biogenesis and low expression of PGC-1α, NRF1, and NRF2 as was demonstrated in human hippocampal neurons as well as in cells overexpressing APP causing familial Alzheimer’s disease [ 37 ]. These data have been later extended to the Aβ toxicity in vitro model where Aβ produced a reduction in Mfn1 and PGC-1α levels, dramatic changes in the mitochondrial network [ 38 ].…”

Nanotechnology-Based Drug Delivery Strategies to Repair the Mitochondrial Function in Neuroinflammatory and Neurodegenerative Diseases

“…The anoma-lous accumulation of protein aggregates impacts mitochondrial structure and function either due to altered interaction with other subcellular organelles or dysregulation of processes involved in mitochondrial dynamics. The main protein aggregates related to proteinopathies are: amyloid β (Aβ) peptide and Tau protein in AD [68][69][70][71]; α-synuclein (α-syn) in PD [72][73][74], transactive response DNA-binding protein of 43 kDa (TDP-43) in AD and ALS [61,75,76]; Cu, Zn-superoxide dismutase (SOD1) in ALS [77,78]; and Huntingtin protein (Htt) in HD [50,79,80]. Table 1 summarizes the evidence relating these protein aggregates with mitochondrial dysfunction in ND diseases.…”

“…Aβ interacts with mitochondrial molecules and structures, which results in ROS production, mitochondrial dysfunction, and subsequent cell damage [91][92][93][94]. In addition, Aβ alters mitochondrial morphology and fragmentation by increasing DRP1 and reducing Mfn1 levels in cellular models [68,94]. Moreover, the mitochondrial fission promoted by Aβ occurs through O-GlcNAcylation of DRP1 in both neuronal cell lines and primary cultured neurons [69].…”