The Adaptor Protein p66Shc Governs Central Nervous System Cell Metabolism and Resistance to Aβ Toxicity
Abstract
Alzheimer’s disease (AD), a progressive and irreversible neurodegenerative disorder, and is the leading cause of dementia worldwide. It has been posited that AD is caused by the gradual deposition of toxic amyloid-b (Ab) plaques in the brain- that cause oxidative stress and eventually leads to neuronal death and synaptic loss. However, multiple therapies that either interfere with the production, or enhance the removal of Ab from the brain, have ultimately failed to slow or prevent AD. With the ever-increasing burden of AD worldwide, there exists an urgent need for novel therapeutic targets. The adult human brain is an energy demanding organ, and numerous studies have shown pronounced reductions in glucose metabolism in AD brains, which precipitates neurodegeneration and memory loss. Specifically, significant losses in brain glycolysis have been observed, while several lines of evidence also demonstrate that the preservation of glycolysis provides key advantages to central nervous system (CNS) cells in AD. However, the mechanisms governing shifts between mitochondrial oxidative phosphorylation (OXPHOS) and glycolysis for ATP generation are poorly understood. Therefore, I aimed to investigate which proteins are involved in promoting metabolic shifts in CNS cells. I focused on p66Shc, an adaptor protein whose canonical functions include apoptotic signalling and ROS production, but recent studies have implicated p66Shc in cellular metabolism. I demonstrate that in cultured CNS cells, expression and activation of p66Shc promotes OXPHOS, increases mitochondrial ROS- and represses glycolytic enzyme expression. p66Shc silencing, however, upregulates glycolytic enzymes, lowers ROS, and protects cells against Ab toxicity. I also determined that p66Shc silencing lowers levels of kelch-like ECH associated protein 1 (KEAP1), which results in increased stabilization of the transcription factor nuclear erythroid 2-related factor 2 (NRF2). Elevated NRF2 promotes increased levels of hypoxia-inducible factor 1α and subsequent elevations in glycolytic enzyme expression. I also showed that protective effects of p66Shc against Ab are NRF2 mediated, and transgenic AD mouse brains have higher p66Shc and KEAP1, but lower NRF2 levels, relative to wildtype mice. Together, these findings reveal a novel mechanism of cellular metabolic regulation, and highlights p66Shc as a potential therapeutic target for the treatment of AD.