Oxidative Stress and the Triangle of Death in Alzheimer Disease Brain: The Aberrant Crosstalk among Energy Metabolism, MTOR Signaling and Protein Homeostasis Revealed by Redox Proteomics
Alzheimer disease (AD) a multifactorial neurodegenerative disorder that represents one of the most disabling conditions in the aged population, shares many features in common with systemic insulin resistance diseases, including reduced insulin stimulated growth and survival signaling, increased oxidative stress, pro inflammatory cytokine activation, mitochondrial dysfunction, impaired energy metabolism and altered protein homeostasis. Reduced glucose utilization and energy metabolism in AD brain is associated with the accumulation of: 1) Ab peptide and hyperphosphorylated tau; 2) increased oxidative stress; 3) unfolded/misfolded proteins. mTOR, aberrantly activated in AD from its earliest stages, plays a key role in AD neurodegeneration by both inhibiting insulin signalling as a negative feedback mechanism and regulating protein homeostasis (synthesis/clearance) Employing the techniques of redox proteomics pioneered in our laboratory led to the identification of oxidatively modified brain proteins in AD involved in concomitant and mutual alterations of energy metabolism, mTOR signaling, and protein homeostasis. These proteins form a self sustaining triangle of harmful events that trigger the degeneration and death of neurons and the development and progression of AD. Moreover, the altered crosstalk among the components of this "triangle of death" beyond altering the redox homeostasis of neurons, is further exacerbated by increased levels of oxidative stress that target and impair key components of the pathways involved, thereby revealing the crucial role of oxidative stress in fueling this aberrant vicious cycle. This triangle of death may represent promising therapeutic targets to slow, delay, or prevent progression of AD.