Role of 4-hydroxy-2-nonenal (HNE) in the pathogenesis of alzheimer disease and other selected age-related neurodegenerative disorders

Fabio Di Domenico, Antonella Tramutola, D. Allan Butterfield

Research output: Contribution to journalReview articlepeer-review

187 Scopus citations


Oxidative stress is involved in various and numerous pathological states including several age-related neurodegenerative diseases. Peroxidation of the membrane lipid bilayer is one of the major sources of free radical-mediated injury that directly damages neurons causing increased membrane rigidity, decreased activity of membrane-bound enzymes, impairment of membrane receptors and altered membrane permeability and eventual cell death. Moreover, the peroxidation of polyunsaturated fatty acids leads to the formation of aldehydes, which can act as toxic by-products. One of the most abundant and cytotoxic lipid -derived aldehydes is 4-hydroxy 2-nonenal (HNE). HNE toxicity is mainly due to the alterations of cell functions by the formation of covalent adducts of HNE with proteins. A key marker of lipid peroxidation, HNE-protein adducts, were found to be elevated in brain tissues and body fluids of Alzheimer disease, Parkinson disease, Huntington disease and amyotrophic lateral sclerosis subjects and/or models of the respective age-related neurodegenerative diseases. Although only a few proteins were identified as common targets of HNE modification across all these listed disorders, a high overlap of these proteins occurs concerning the alteration of common pathways, such as glucose metabolism or mitochondrial function that are known to contribute to cognitive decline. Within this context, despite the different etiological and pathological mechanisms that lead to the onset of different neurodegenerative diseases, the formation of HNE-protein adducts might represent the shared leit-motif, which aggravates brain damage contributing to disease specific clinical presentation and decline in cognitive performance observed in each case.

Original languageEnglish
Pages (from-to)253-261
Number of pages9
JournalFree Radical Biology and Medicine
StatePublished - Oct 2017

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.


  • 4-hydroxy-2-nonenal
  • Alzheimer disease
  • Amyotrophic lateral sclerosis
  • Huntington disease
  • Lipid peroxidation
  • Michael adducts
  • Parkinson disease
  • Redox proteomics

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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