The Butterfield laboratory studies free radical oxidative stress in aging and age-related neurodegenerative disorders, particularly Alzheimer's disease (AD). We discovered in AD brain that such oxidative stress is manifested  by protein oxidation, lipid peroxidation, reactive oxygen species (ROS) production, mitochondrial dysfunction, and functional impairment of key transmembrane transport proteins, among many others. Our laboratory studies these and other aspects of oxidative stress in brain membranes using a variety of techniques, including immunochemical, metabolomic, and proteomics methods. Our group first described how oxidative stress associated with amyloid  β-peptide, a 42-amino acid peptide deposited in AD brains, leads to neurotoxicity and how various antioxidants can modulate or prevent this oxidative stress and neuronal death. Insight into the molecular basis for and potential therapeutic interventions in aging and age-related neurodegenerative disorders is envisaged from our research. Recent research has emphasized the close connection between Type 2 diabetes mellitus and development of AD.  We found that brain from subjects with AD and for the first time in arguably AD’s earlier form, Mild Cognitive Impairment (MCI), strong evidence of insulin resistance, which contributes to the metabolic changes in brain well known in AD.

Our laboratory pioneered the techniques of redox proteomics (see figure below) to identify oxidatively modified brain proteins in subjects with AD and MCI. Proteins identified have provided new insights into molecular processes involved in mechanisms of neuronal death in and progression of AD.

Processes involved in redox proteomics, which is used to identify oxidatively modified brain proteins in Alzheimer's disease and other neurodegenerative disorders.

In a second area of research, the Butterfield laboratory discovered a mechanism for chemotherapy induced cognitive impairment (CICI), which lowers the quality of life for up to 70 percent of the currently 14 million cancer survivors in the USA.  Diminished executive functioning, inability to multitask, and slowness in mental processing, called “chemobrain” by patients, often are complaints described by persons with CICI.  Metabolic analyses using Seahorse technology and MS-based methods suggest mitochondrial dysfunction and apoptosis in brain following chemotherapy involving ROS associated chemotherapeutic agents, even though these agents do not cross the blood-brain barrier. We found an important inflammatory cytokine is elevated in plasma, and this harmful molecule does cross the BBB to initiate a series of harmful biochemical processes in brain.  Highly innovative studies using a variety of biochemical and chemical techniques are shedding light on how to prevent CICI, with the strong possibility that the quality of life of cancer survivors will be enhanced.