Nrf2 activation through the PI3K/GSK-3 axis protects neuronal cells from Aβ-mediated oxidative and metabolic damage

Abstract

Background: Mounting evidence points to a crucial role of amyloid-β (Aβ) 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 Aβ, 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 oligAβ in SH-SY5Y and primary neurons testing their pharmacologic protection by small molecules.Results: Our findings indicate that oligomeric Aβ induces a dramatic increase in ROS production and severely affects neuronal metabolism and bioenergetics. Assessment of global energy metabolism in real time demonstrated Aβ-mediated reduction in oxygen consumption affecting basal and maximal respiration and causing decreased ATP production. Pharmacologic targeting of Aβ-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 Nrf2compromised 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 Aβ protective action. Conclusions:Our study provides insights into the complex molecular mechanisms triggered by oligAβ 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.

Dietary Antioxidants and Parkinson’s Disease

“…δ-tocotrienol binds to the estrogen receptor β and activates PI3K/Akt signaling pathways including phosphorylation of protein kinase B (PKB, Akt) and extracellular signal-regulated kinase (ERK) 1/2 [ 128 , 168 ]. Akt activates Nrf2 [ 169 , 170 ], and Nrf2-mediated upregulation of antioxidant and prosurvival genes is an important mechanism for the neuroprotective properties of many antioxidant nutrients [ 171 , 172 , 173 ]. Clinical studies with PD patients show that higher consumption of dietary vitamin E is inversely related to PD occurrence [ 157 , 164 , 174 , 175 ].…”

Intersection between Redox Homeostasis and Autophagy: Valuable Insights into Neurodegeneration

“…Some studies reported the potential role of Aβ monomers as antioxidants, depending on the metal ion concentration in vitro [ 49 , 50 ]. In contrast, other studies showed that oligomeric Aβ, the dominant form in patients with AD, promotes ROS production in cooperation with metal ions in vitro and in vivo [ 51 , 52 , 53 , 54 ]. In addition, inhibition of the γ-secretase activity was reported to reduce the levels of ROS and oxidize proteins, and to enhance resistance to oxidative stress [ 55 ].…”

“…In addition, inhibition of the γ-secretase activity was reported to reduce the levels of ROS and oxidize proteins, and to enhance resistance to oxidative stress [ 55 ]. Aβ activates NADPH oxidase and interferes with Ca 2+ homeostasis and mitochondrial membrane potential, leading to impaired ROS homeostasis [ 53 , 56 , 57 , 58 ]. Tau neurofibrillary tangles, which contain oxidized molecules, also produce ROS by interacting with Cu 2+ , which in turn increases the formation of tau aggregates [ 59 ].…”

Bisdemethoxycurcumin inhibits oxidative stress and antagonizes Alzheimer's disease by up‐regulating SIRT1

“…At present, the most accepted theory attributes a major role to the aberrant production and accumulation of protein aggregates, including different amyloid‐β (Aβ) peptides (Ishida et al., 2020). However, the exact cellular and molecular mechanisms underlying this disorder remain unclear (Sotolongo, Ghiso, & Rostagno, 2020) The current medications for AD are mainly cholinesterase inhibitors (including donepezil, galantamine, rivastigmine) and N‐methyl‐D‐receptor antagonists (memantine; Rygiel, 2016), which can only alleviate symptoms. There are still no effective treatments to prevent, halt, or reverse AD (Huang & Mucke, 2012).…”