CoChat
Sign Up
Cited by 126Alzheimer's disease research and treatmentsRedox biology and oxidative stressCancer-related cognitive impairment studies

The 2013 SFRBM Discovery Award: Selected discoveries from the Butterfield laboratory of oxidative stress and its sequela in brain in cognitive disorders exemplified by Alzheimer disease and chemotherapy induced cognitive impairment

Open access
Butterfield, D. Allan·2014·Free Radical Biology and Medicine
DOI 10.1016/j.freeradbiomed.2014.06.006PMC PMC4146642
Open this paper in CoChat — free account

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/j.freeradbiomed.2014.06.006

Cites

181 of 181 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Oxidative and nitrosative stress are critical factors in the pathogenesis and progression of Alzheimer disease and amnestic mild cognitive impairment.

    “Oxidative and nitrosative stress are widely recognized as critical factors in the pathogenesis and progression of Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI).”

    From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [12]

    Section 3.1 identifies oxidative stress as a component of AD pathogenesis and progression, and section 3.2 reports elevated oxidative markers and 3-nitrotyrosine in both AD and amnestic MCI. The paper does not establish nitrosative stress as a critical factor in the pathogenesis and progression of both conditions; its explicit discussion of a causal role for nitrosative stress is in chemotherapy-induced cognitive impairment (section 4.3). Page numbers were not available in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Many of the oxidized proteins identified are mitochondrial proteins involved in metabolism, protein synthesis and folding, ROS scavenging, transport, and apoptosis.

    “Consistent with the hypothesis that both oxidative stress and mitochondrial dysfunction are early events in the progression of AD [12,35,53], many of the oxidized proteins identified are mitochondrial proteins involved in metabolism, protein synthesis and folding, ROS scavenging, transport, and apoptosis (Table 1).”

    From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [12]

    Section 3.2 (page unavailable) identifies oxidatively modified proteins in AD or aMCI brain involved in metabolism, chaperone activity, antioxidant defense, apoptosis, and protein synthesis. It also names TCA enzymes and ATP-synthase components. The copy does not establish that many of the identified proteins are mitochondrial or document the full list as functions of mitochondrial proteins; its transport example in section 3.6 is a glutamate transporter. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Redox proteomics has led to identification of oxidized proteins, indexed by carbonylation, nitration, and modification with HNE, in in vitro and in vivo models of AD and in MCI and AD brain.

    “As mentioned above, the use of redox proteomics has led to the identification of oxidized proteins, as indexed by carbonylation, nitration, and modification with HNE, in both in vitro and in vivo models of AD in addition to MCI and AD brain.”

    From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [12]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. [87]Yatin SM Varadarajan S Link CD Butterfield DA In vitro and in vivo oxidative stress associated with Alzheimer's amyloid beta-peptide (1-42) Neurobiol Aging 20 325 330 discussion 339-342 1999 10588580
  2. [152]Butterfield DA Swomley AM Sultana R Amyloid beta-Peptide (1-42)-Induced Oxidative Stress in Alzheimer Disease: Importance in Disease Pathogenesis and Progression Antioxid Redox Signal 19 823 835 2013 23249141 PMC3749710
  3. [160]Raffa RB Tallarida RJ Chemo-Fog Landis Biosci. Press Austin 2010

Cited by

Sorted by citations

Related

Authors
Butterfield, D. A.
Affiliations
University of Kentucky (US)
Corresponding author
Butterfield, D. Allan
ORCID
Butterfield, D. Allan
Venue
Free Radical Biology and Medicine
Publisher
Elsevier BV
Published
2014-09
Volume
74
Pages
157-174
ISSN
0891-5849 (ISSN-L)
DOI
10.1016/j.freeradbiomed.2014.06.006
PMC
PMC4146642
OpenAlex
W2052411522
Cited by
126
References
181
Citations by year
2026: 2 · 2025: 9 · 2024: 11 · 2023: 10 · 2022: 12 · 2021: 15 · 2020: 16 · 2019: 12 · 2018: 15 · 2017: 5 · 2016: 8 · 2015: 10 · 2014: 1
FWCI
0.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Free Radical Biology and Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
UK Markey Cancer Center
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cancer-related cognitive impairment studies
Keywords
Alzheimer's disease, chemotherapy-induced cognitive impairment, oxidative stress, amyloid-beta, protein oxidation, lipid peroxidation, redox proteomics, doxorubicin, apolipoprotein A-I, TNF-α, blood-brain barrier, mitochondrial dysfunction, apoptosis, chemobrain, free radicals, brain aging, cognitive disorders, amyloid precursor protein, neuroinflammation
MeSH terms
Alzheimer Disease, Animals, Antineoplastic Agents, Cognition Disorders, Disease Models, Animal, Humans, Oxidation-Reduction, Peptide Fragments, Lipid Peroxidation, Amyloid beta-Peptides, Oxidative Stress, Protein Multimerization, Drug-Related Side Effects and Adverse Reactions

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review