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Chemistry Department Guest Lecture Series
September 13, 2018 @ 11:00 am - 12:00 pm
Dr. D. Allan Butterfield of the University of Kentucky Chemistry Department for a special presentation entitled:
OXIDATIVE STRESS AND THE PROGRESSION OF ALZHEIMER DISEASE: THE TRIANGLE OF DEATH FOR NEURONS ASSOCIATED WITH GLUCOSE DYSMETABOLISM, mTOR ACTIVATION, and ALTERED PROTEIN PHOSPHORYLATION REVEALED BY 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 signalling, 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) Aβ 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 glucose metabolism, mTOR signalling, and protein phosphorylation. 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. Support: Grants from NIH.