Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aß-mediated oxidative and metabolic damage.
Alzheimers Res Ther
; 12(1): 13, 2020 01 13.
Article
em En
| MEDLINE
| ID: mdl-31931869
ABSTRACT
BACKGROUND:
Mounting evidence points to a crucial role of amyloid-ß (Aß) in the pathophysiology of Alzheimer's disease (AD), a disorder in which brain glucose hypometabolism, downregulation of central elements of phosphorylation pathways, reduced ATP levels, and enhanced oxidative damage coexist, and sometimes precede, synaptic alterations and clinical manifestations. Since the brain has limited energy storage capacity, mitochondria play essential roles in maintaining the high levels of energy demand, but, as major consumers of oxygen, these organelles are also the most important generators of reactive oxygen species (ROS). Thus, it is not surprising that mitochondrial dysfunction is tightly linked to synaptic loss and AD pathophysiology. In spite of their relevance, the mechanistic links among ROS homeostasis, metabolic alterations, and cell bioenergetics, particularly in relation to Aß, still remain elusive.METHODS:
We have used classic biochemical and immunocytochemical approaches together with the evaluation of real-time changes in global energy metabolism in a Seahorse Metabolic Analyzer to provide insights into the detrimental role of oligAß in SH-SY5Y and primary neurons testing their pharmacologic protection by small molecules.RESULTS:
Our findings indicate that oligomeric Aß induces a dramatic increase in ROS production and severely affects neuronal metabolism and bioenergetics. Assessment of global energy metabolism in real time demonstrated Aß-mediated reduction in oxygen consumption affecting basal and maximal respiration and causing decreased ATP production. Pharmacologic targeting of Aß-challenged neurons with a set of small molecules of known antioxidant and cytoprotective activity prevented the metabolic/bioenergetic changes induced by the peptide, fully restoring mitochondrial function while inducing an antioxidant response that counterbalanced the ROS production. Search for a mechanistic link among the protective small molecules tested identified the transcription factor Nrf2-compromised by age and downregulated in AD and transgenic models-as their main target and the PI3K/GSK-3 axis as the central pathway through which the compounds elicit their Aß protective action.CONCLUSIONS:
Our study provides insights into the complex molecular mechanisms triggered by oligAß which profoundly affect mitochondrial performance and argues for the inclusion of small molecules targeting the PI3K/GSK-3 axis and Nrf2-mediated pathways as part of the current or future combinatorial therapies.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Peptídeos beta-Amiloides
/
Estresse Oxidativo
/
Fator 2 Relacionado a NF-E2
/
Mitocôndrias
/
Neurônios
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Alzheimers Res Ther
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Estados Unidos