Redox proteomics identification of 4‐hydroxynonenal‐modified brain proteins in Alzheimer's disease: Role of lipid peroxidation in Alzheimer's disease pathogenesis

Abstract

Numerous studies have shown that neuronal lipids are highly susceptible to oxidative stress including in those brain areas directly involved in the neurodegenerative process of Alzheimer’s disease (AD). Lipid peroxidation directly damages membranes and also generates a number of secondary biologically active products (toxic aldehydes)that are capable of easily attacking lipids, proteins, and DNA. Accumulating evidence has demonstrated regionally increased brain lipid peroxidation in patients with AD; however, extensive studies on specific targets of lipid peroxidation-induced damage are still missing. The present study represents a further step in understanding the relationship between oxidative modification of protein and neuronal death associated with AD. We used a proteomics approach to determine specific targets of lipid peroxidation in AD brain, both in hippocampus and inferior parietal lobule, by coupling immunochemical detection of 4-hydroxynonenal-bound proteins with 2-D polyacrylamide gel electrophoresis and MS analysis. We identified 4-hydroxynonenal-bound proteins in the hippocampus and inferior parietal lobule brain regions of subjects with AD. The identified proteins play different biological functions including energy metabolism, antioxidant system, and structural proteins, thus impairing multiple molecular pathways. Our results provide further evidence for the role of lipid peroxidation in the pathogenesis of AD.

Redox Proteomics in Selected Neurodegenerative Disorders: From Its Infancy to Future Applications

“…Reduced levels of ATP strengthen the rationale that energy metabolism is altered in AD (160). ATP synthase has been previously shown to be oxidatively modified in late-stage AD (304). The oxidation of ATP synthase leads to the inactivation of this mitochondrial complex.…”

“…In late-stage AD, redox proteomics identified four HNEmodified proteins that overlap EAD (Eno1, ATP synthase, MnSOD, and CRMP2) (304,322). Both Eno1 and ATP synthase are consistently HNE modified in all transitional stages of AD, providing evidence for the altered energy metabolism and mitochondrial dysfunction hypotheses associated in the progression of AD (66,160,175).…”

“…The three cysteine residues in the Fe-S core can undergo Michael addition and form acrolein, HNE, and maldondialdehyde conjugated adducts, thereby increasing lipid peroxidation markers (248,350). Enzymatic activity of this enzyme is significantly reduced in AD, thereby yielding in protein dysfunction (304). The TCA cycle takes place in the mitochondria; therefore, aconitase impairment results in mitochondrial dysfunction, a common theme of neurodegenerative diseases (405).…”

Aldehyde Dehydrogenase: Cancer and Stem Cells

“…Overconsumption of ethanol has been related to liver disease and several gastrointestinal and upper aerodigestive cancers. Numerous other cytotoxic and reactive aldehydes have been shown to be linked with other types of diseases (Hofseth & Wargovich, 2007, Perluigi, et al, 2009, Chen, et al, 2010.…”

Oxidative Stress and Proteostasis Network: Culprit and Casualty of Alzheimer’s-Like Neurodegeneration

“…Several studies have provided indirect evidence that suggests that alterations in protein synthesis may occur in AD [100,101]. Redox proteomics studies demonstrated that EFTu and eukaryotic initiation factor (eIF-) are HNEmodified in the IPL of MCI brain [102]. EF-Tu and eIF-are intimately involved in protein synthesis machinery.…”