Abstract
A key pathological feature of Alzheimer’s disease (AD) is the accumulation of the neurotoxic amyloid beta (Aβ) peptide within the brains of affected individuals. Previous studies have shown that neuronal cells selected for resistance to Aβ toxicity display a metabolic shift from mitochondrial-dependent oxidative phosphorylation (OXPHOS) to aerobic glycolysis to meet their energy needs. The Src homology/collagen (Shc) adaptor protein p66Shc is a key regulator of mitochondrial function, ROS production and aging. Moreover, increased expression and activation of p66Shc promotes a shift in the cellular metabolic state from aerobic glycolysis to OXPHOS in cancer cells. Here we evaluated the hypothesis that activation of p66Shc in CNS cells promotes both increased OXPHOS and enhanced sensitivity to Aβ toxicity. The effect of altered p66Shc expression on metabolic activity was assessed in rodent HT22 and B12 cell lines of neuronal and glial origin respectively. Overexpression of p66Shc repressed glycolytic enzyme expression and increased both mitochondrial electron transport chain activity and ROS levels in HT22 cells. The opposite effect was observed when endogenous p66Shc expression was knocked down in B12 cells. Moreover, p66Shc activation in both cell lines increased their sensitivity to Aβ toxicity. Our findings indicate that expression and activation of p66Shc renders CNS cells more sensitive to Aβ toxicity by promoting mitochondrial OXPHOS and ROS production while repressing aerobic glycolysis. Thus, p66Shc may represent a potential therapeutically relevant target for the treatment of AD.
Highlights
Alzheimer’s disease (AD) is a chronic, neurodegenerative disorder that is characterized by a gradual development of cognitive dysfunction and memory loss
Cells selected for amyloid β peptide (Aβ) resistance in vitro exhibit increased glucose consumption and lactate production, as well as significantly higher expression of pyruvate kinase, hexokinase, lactate dehydrogenase (LDHA), and pyruvate dehydrogenase kinase 1 (PDK1); enzymes involved in aerobic glycolysis[23,24,29,30]
All ShcA isoforms are phosphorylated at tyrosine residues in response to growth factor signaling, p66Shc is phosphorylated at serine 36 (S36) within the collagen homology 2 (CH2) domain by kinases that are activated in response to various oxidative stressors[35,36,37,38]
Summary
In this study we demonstrate that the expression and activation of p66Shc in CNS cells significantly increases OXPHOS, while downregulating aerobic glycolysis. Cells selected for resistance to Aβ toxicity exhibit both an increase in both glycolytic and antioxidant enzyme expression; proteins repressed by activated p66Shc[23,24,29]. In the context of aging, adult wild type mice exhibit a significant increase in both p66Shc protein levels and S36 phosphorylation in multiple tissues when compared to newborns; events associated with higher mitochondrial H2O2 production[93]. Deletion of the p66Shc gene in mice leads to an improvement in age-dependent cognitive decline, as well as significant increases in levels of the neurotrophin brain derived neurotrophic factor (BDNF) in the hippocampus and sustained hippocampal neurogenesis[113,114]. Silencing p66Shc expression shifts the metabolic state of a cell away from OXPHOS and towards aerobic glycolysis, thereby lowering ROS levels and promoting stress resistance against Aβ. Our findings suggest that agents which either target p66Shc, including upstream activating kinases, or drugs which enhance aerobic glycolysis may have therapeutic relevance for the treatment of AD and possibly other age-dependent neurodegenerative disorders
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