ReviewBrain lipid peroxidation and alzheimer disease: Synergy between the Butterfield and Mattson laboratories
Introduction
This review focuses on lipid peroxidation in brains of persons with Alzheimer disease (AD) and its earlier stage, amnestic mild cognitive impairment (MCI). More specifically, this review focuses on the lipid peroxidation product, 4-hydroxy-2-nonenal (HNE), and the changes in structure and function of brain proteins in AD and MCI relative to those control brains that this highly reactive and neurotoxic alkenal engenders. This review also focuses on the roles of HNE associated with amyloid β-peptide (Aβ) oligomers in AD-relevant in vitro, ex vivo, and in vivo systems reported by the Butterfield and/or Mattson laboratories. This emphasis is apropos given that this paper is part of a Special Issue of the journal, Ageing Research Reviews honoring Mark P. Mattson for his distinguished scientific career in these fields.
Section snippets
Epidemiology, Pathophysiology, and Pathogenesis
An authoritative pathological exposition of AD and MCI has been reported by Nelson and Markesbery (Nelson et al., 2009; Markesbery, 2007a,b; Markesbery, 2010) or other neuropathologists (Landau and Frosch, 2014; Malek-Ahmadi et al., 2018). The sixth leading cause of death in the United States, AD presents as a disorder associated with progressive loss of cognitive function finally ending in dementia. In later stages of AD, aphasia often occurs. AD patients often are restless, unsettled, and
Aβ and lipid peroxidation: first evidence
Arguably, the first demonstration of lipid peroxidation induced by Aβ employed electron paramagnetic resonance (EPR) methods (Butterfield et al., 1994). A lipid bilayer-soluble stearic acid spin label, which contains a sterically protected nitroxide moiety from which the EPR spectrum arises, was added to a gerbil synaptosomal preparation. Addition of Aβ to synaptosomes prepared from gerbils led to diminution of the intensity of this EPR spectrum. This phenomenon arises because a lipid centered
AD-related In Vivo or Ex Vivo Studies Involving Aβ and Lipid Peroxidation
Table 1 shows selected examples of AD-related in vivo or ex vivo studies involving Aβ from the Butterfield and Mattson laboratories. The main takeaways from these studies are:
- a)
Aβ42 and lipid peroxidation are intimately associated. This association makes sense, as this hydrophobic, oligomeric peptide intercalates into the lipid bilayer, in which there are copious amounts of labile lipid allylic H-atoms that can be extracted by a radical, leading to a cascade of events that culminates in
Redox Proteomics, Glucose Dysmetabolism, and AD
Redox proteomics is that branch of proteomics that is used to identify oxidatively modified proteins (Butterfield et al., 2012; Butterfield et al., 2014b; Butterfield and Boyd-Kimball, 2019). In essentially all oxidatively modified brain proteins, loss of activity of such proteins was observed. Loss of activity likely results from either oxidative modification of active site amino acids (e.g., cysteine; serine) and/or structural changes to oxidized proteins caused by oxidative modification of
Synergy of Studies between the Butterfield and Mattson Laboratories
The highly reactive and neurotoxic product of lipid peroxidation, HNE, by covalently binding to and modifying the structure and function of target proteins in brains of persons with AD, MCI, or animal models thereof, contributes significantly to the pathology, biochemistry, and clinical presentation of AD and its earlier stages, as described above. The Butterfield laboratory for the most part has focused on oxidative damage, with emphasis on lipid peroxidation and its sequale, in AD and MCI
Brief Reflections on Mark Mattson and His Outstanding Career
While he was at the University of Kentucky, Mark Mattson and I became very good friends and colleagues, and we remain so. We were both recruited to be part of the Sanders-Brown Center on Aging by the founder of this Center, Dr. William R. Markesbery, who also was a gifted Alzheimer disease researcher, clinician, and neuropathologist. Mark and I talked often of research ideas and plans, and we were separate Project Leaders together on two NIA-funded P01 Program Project Grants headed by Dr.
Acknowledgements
The author thanks the faculty of Sanders-Brown Center on Aging at the University of Kentucky for providing well-characterized specimens from AD, MCI, preclinical AD and brains and those from corresponding aged-matched controls, obtained at a quite short post-mortem interval for studies in our laboratory that are referenced in the current paper. The author thanks Dr. Xiaojia Ren for preparation of figures for this paper. This work was supported in part by grants from the National Institutes of
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