Neuronal Membrane Lipid Peroxidation and Alzheimer Disease: Role of Amyloid &beta-Peptide-Induced Alterations in Glucose Metabolism in AD Pathogenesis and Progression

This Keynote Symposium address, dedicated to the enormous contributions to membrane science made by Dr. Elias Klein, will emphasize the intersection of oxidative damage in brain, coupled to decreased glucose metabolism and thinning of cortical and hippocampal brain areas, that revolve around membrane lipid bilayer peroxidation in neurons in Alzheimer disease (AD). Representing the greatest proportion of dementia worldwide, AD is an age-related, progressive disorder characterized pathologically by deposition of fibrillar aggregates (senile plaques) composed mostly of the 42-amino acid peptide, amyloid beta-peptide (Ab42), and hyperphosphorylated tau protein (neurofibrillary tangles), along with loss of synapes and neurons. Our laboratory first showed oxidative damage to proteins and lipids, associated with Ab42 small oligomers (dimers, trimers, etc.) inserted in the neuronal membrane lipid bilayer [1]. Membrane lipid peroxidation was the first oxidative damage observed, producing the highly reactive alpha,beta-unsatured aldehyde, 4-hydroxy-2-nonenal (HNE) [2]. By Michael addition, HNE forms covalent adducts with Cys, His, and Lys residues on various proteins, including enzymes, changing their conformation and causing dysfunction [3].
Type 2 diabetes mellitus (T2DM) and its insulin resistance are associated with, among many other detrimental biochemical problems, decreased glucose utilization [4]. The brain utilizes glucose for its primary energy source, and in brain from persons with AD and its early stage, amnestic mild cognitive impairment (aMCI), progressively decreased glucose metabolism in brain is observed. Indeed, T2DM is a major risk factor for development of AD [4].
Using redox proteomics, a technique pioneered in our laboratory [5] and facilitated by the proteomics facility directed by Dr. Jon B. Klein, the son of Dr. Elias Klein, and his colleagues, we identified several glycolytic and TCA enzymes as well as ATP synthase that are oxdidatively damaged by HNE with resultant lower function [6]. The consequent loss of cell potential due to decreased ATP opens voltage-gated calcium channels, causing a large increase in intracellular calcium ions, leading through a series of neurochemical processes to death of neurons.
Several years ago, our laboratory hypothesized that this sequence of events, e.g., Ab42 oligomeric-mediated lipid peroxidation of neurons leads to decreased glucose metabolism that leads to neuronal death indexed by thinning of cortical and hippocampal structures of the brain, was the basis of aMCI and AD [1,2,6]. In early 2018, a paper was published [7] reporting results of using PET scanning for Ab42, PET scanning for glucose metabolism, and MRI to determine thickness of cortical and hippocampal brain structures over time in persons with inherited AD. The period for repeated observations spanned 22 years prior to the onset of symptoms to three years after symptoms appeared (25 years total). The sequence of reported changes in brains of these individuals with autosomal dominantly inherited AD was: a) deposition of Ab42 (meaning that Ab42 oligomers would be present and solubilized in neuronal membranes to initiate membrane lipid peroxidation); b) followed by dysfunction of glucose metabolism; and, finally, c) by thinning of cortical and hippocampal brain regions. That is, this exciting study confirmed the predictions of our overall hypothesis on the molecular events and their sequence in the pathogenesis and progression of AD. Implications of our studies include identification of potential therapeutic targets to slow or stop the onset and progression of this devastating dementing disorder.
This work was supported by grants from NIH.

References

[1] D.A. Butterfield, J. Drake, C. Pocernich, and A. Castegna (2001) Evidence of Oxidative Damage in Alzheimer's Disease Brain: Central Role of Amyloid b-Peptide. Trends Molec Med. 7, 548-554.

[2] R. Sultana, M. Perluigi, and D.A. Butterfield (2013) Lipid Peroxidation Triggers Neurodegeneration: A Redox Proteomics View into the Alzheimer Disease Brain. Free Radic Biol Med 62,157-169.

[3] R. Subramaniam, F. Roediger, B. Jordan, M.P. Mattson, J.N. Keller, G. Waeg, and D.A. Butterfield (1997) The Lipid Peroxidation Product, 4-Hydroxy-2-Trans-Nonenal, Alters the Conformation of Cortial Synaptosomal Membrane Proteins. J Neurochem. 69, 1161-1169.

[4] D. A. Butterfield, F. Di Domenico, and E. Barone (2014) Elevated Risk of Type 2 Diabetes for Development of Alzheimer Disease: a Key Role for Oxidative Stress in Brain. Biochim Biophys Acta 1842,1693-1706.

[5] D.A. Butterfield, M. Perluigi, T. Reed, T. Muharib, C. Hughes, R. Robinson, and R. Sultana (2012) Redox Proteomics in Selected Neurodegenerative Disorders. From its Infancy to Future Applications. Antioxidant Redox Signal 17,1610-1655.

[6[ F. Di Domenico, A. Tramutola, and D.A. Butterfield (2017) Role of 4-Hydroxy-2-Nonenal (HNE) in the Pathogenesis of Alzheimer Disease and Other Selected Age-Related Neurodegenerative Disorders. Free Radic Biol Med 111, 253-261.

[7] Gordon BA, Blazey TM, Su Y, Hari-Raj A, Dincer A, Flores S, Christensen J, McDade E, Wang G, Xiong C, Cairns NJ, Hassenstab J, Marcus DS, Fagan AM, Jack, Jr CR, Hornbeck RC, Paumier KL, Ances BM, Berman SB, Brickman AM, Cash DM, Chhatwal JP, Correia S, Forster S, Fox NC, Graff-Radford NR, la Fougere C, Levin J, Masters CL, Rossor MN, Salloway S, Saykin AJ, Schofield PR, Thompson PM, Weiner MM, Holtzman DM, Raichle ME, Morris JC, Bateman RJ, Benzinger TL (2018) Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study. Lancet Neurol 17,241-250.