Redox proteomics analysis of HNE-modified proteins in Down syndrome brain: Clues for understanding the development of Alzheimer disease

Fabio Di Domenico, Gilda Pupo, Antonella Tramutola, Alessandra Giorgi, Maria Eugenia Schininà, Raffaella Coccia, Elizabeth Head, D. Allan Butterfield, Marzia Perluigi

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Down syndrome (DS) is the most common genetic cause of intellectual disability, due to partial or complete triplication of chromosome 21. DS subjects are characterized by a number of abnormalities including premature aging and development of Alzheimer disease (AD) neuropathology after approximately 40 years of age. Several studies show that oxidative stress plays a crucial role in the development of neurodegeneration in the DS population. Increased lipid peroxidation is one of the main events causing redox imbalance within cells through the formation of toxic aldehydes that easily react with DNA, lipids, and proteins. In this study we used a redox proteomics approach to identify specific targets of 4-hydroxynonenal modifications in the frontal cortex from DS cases with and without AD pathology. We suggest that a group of identified proteins followed a specific pattern of oxidation in DS vs young controls, probably indicating characteristic features of the DS phenotype; a second group of identified proteins showed increased oxidation in DS/AD vs DS, thus possibly playing a role in the development of AD. The third group of comparison, DS/AD vs old controls, identified proteins that may be considered specific markers of AD pathology. All the identified proteins are involved in important biological functions including intracellular quality control systems, cytoskeleton network, energy metabolism, and antioxidant response. Our results demonstrate that oxidative damage is an early event in DS, as well as dysfunctions of protein-degradation systems and cellular protective pathways, suggesting that DS subjects are more vulnerable to oxidative damage accumulation that might contribute to AD development. Further, considering that the majority of proteins have been already demonstrated to be oxidized in AD brain, our results strongly support similarities with AD in DS.

Original languageEnglish
Pages (from-to)270-280
Number of pages11
JournalFree Radical Biology and Medicine
StatePublished - Jun 2014

Bibliographical note

Funding Information:
This work was partially supported by NIH grant to D.A.B. (A6-05119). Brain tissue was acquired by E.H. under funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development , National Institute on Aging Grant NIH 1RO1HD064993-01 . Additional autopsy tissue was obtained from the UCI-ADRC (P50AG16573), from the UK ADC (P30AG28383), and from the NICHD Brain and Tissue Bank for Developmental Disorders of the University of Maryland (Baltimore, MD, USA), Contract HHSN275200900011C (N01HD90011). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.


  • Alzheimer disease
  • Down syndrome
  • Free radicals
  • HNE
  • Lipid peroxidation
  • Protein oxidation
  • Redox proteomics
  • Trisomy 21

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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