This retrospective review on discoveries of the roles of oxidative stress in brain of subjects with Alzheimer disease (AD) and animal models thereof as well as brain from animal models of chemotherapy-induced cognitive impairment (CICI) results from the author receiving the 2013 Discovery Award from the Society for Free Radical Biology and Medicine. The paper reviews our laboratory's discovery of protein oxidation and lipid peroxidation in AD brain regions rich in amyloid β-peptide (Aβ) but not in Aβ-poor cerebellum; redox proteomics as a means to identify oxidatively modified brain proteins in AD and its earlier forms that are consistent with the pathology, biochemistry, and clinical presentation of these disorders; how Aβ in in vivo, ex vivo, and in vitro studies can lead to oxidative modification of key proteins that also are oxidatively modified in AD brain; the role of the single methionine residue of Aβ(1-42) in these processes; and some of the potential mechanisms in the pathogenesis and progression of AD. CICI affects a significant fraction of the 14 million American cancer survivors, and due to diminished cognitive function, reduced quality of life of the persons with CICI (called "chemobrain" by patients) often results. A proposed mechanism for CICI employed the prototypical ROS-generating and non-blood brain barrier (BBB)-penetrating chemotherapeutic agent doxorubicin (Dox, also called adriamycin, ADR). Because of the quinone moiety within the structure of Dox, this agent undergoes redox cycling to produce superoxide free radical peripherally. This, in turn, leads to oxidative modification of the key plasma protein, apolipoprotein A1 (ApoA1). Oxidized ApoA1 leads to elevated peripheral TNFα, a proinflammatory cytokine that crosses the BBB to induce oxidative stress in brain parenchyma that affects negatively brain mitochondria. This subsequently leads to apoptotic cell death resulting in CICI. This review outlines aspects of CICI consistent with the clinical presentation, biochemistry, and pathology of this disorder. To the author's knowledge this is the only plausible and self-consistent mechanism to explain CICI. These two different disorders of the CNS affect millions of persons worldwide. Both AD and CICI share free radical-mediated oxidative stress in brain, but the source of oxidative stress is not the same. Continued research is necessary to better understand both AD and CICI. The discoveries about these disorders from the Butterfield Laboratory that led to the 2013 Discovery Award from the Society of Free Radical and Medicine provide a significant foundation from which this future research can be launched.
|Number of pages||18|
|Journal||Free Radical Biology and Medicine|
|State||Published - Sep 2014|
Bibliographical noteFunding Information:
The results noted in this paper were obtained with support by NIH grants and by funds from the UK Markey Cancer Center . The 2013 Discovery Award from the Society for Free Radical Biology and Medicine was presented to me for discoveries that emanated from my laboratory related to fundamental free radical processes in both AD and CICI. However, I am first to state that this recognition is in large part due to the great fortune and opportunity I have had to train immensely talented and motivated Ph.D., M.S., and undergraduate students, postdoctoral scholars, and visiting scientists, as well as collaborate with generous and supportive faculty at the University of Kentucky and elsewhere. It is to this entire group of wonderful people that I am grateful and appreciative. The 2013 Discovery Award from the Society for Free Radical Biology and Medicine is a highlight of my career. I would like to mention a few University of Kentucky collaborators for special thanks. First I wish to acknowledge the late William R. Markesbery, M.D., a consummate gentleman and outstanding neuropathologist, who made a number of seminal contributions to the field of AD and provided me with important guidance throughout my career. Others to thank for their assistance and collaboration with my laboratory in the field of AD include Mark Mattson, Ph.D., James Geddes, Ph.D., Stephen Scheff, Ph.D., Steven Estus, Ph.D., M. Paul Murphy, Ph.D., Elizabeth Head, Ph.D., Peter Nelson, M.D., and Linda Van Eldik, Ph.D. In our studies of CICI, I thank Daret K. St. Clair, Ph.D., Jeffrey A. Moscow, M.D., Mary Vore Iwamoto, Ph.D., John Hayslip, M.D., Heidi Weiss, Ph.D., Subbaro Bondada, Ph.D., and B. Mark Evers, M.D., each a highly respected scientist or physician-scientist. Together we formed a team, without which our progress in CICI could not have occurred. This group provided enormous assistance and friendship for which I will always be grateful.
- 2013 SFRBM Discovery Award
- Alzheimer disease (AD) and its earlier forms (amnestic MCI and preclinical AD)
- Aβ(1-42) associated oxidative stress
- Chemotherapy-induced cognitive impairment (" chemobrain")
- Plasma-derived elevated TNFα and its sequela in brain
- Redox proteomics
ASJC Scopus subject areas
- Physiology (medical)