Neuronal oxidative stress precedes amyloid-β deposition in down syndrome

Akihiko Nunomura, George Perry, Miguel A. Pappolla, Robert P. Friedland, Keisuke Hirai, Shigeru Chiba, Mark A. Smith

Research output: Contribution to journalArticle

268 Scopus citations

Abstract

The predictable chronological sequence of pathological events in Down syndrome (DS) provides the opportunity to rigorously investigate the relationship between oxidative stress and amyloid-β (Aβ) deposition. In this study, we report a marked accumulation of oxidized nucleic acid, 8-hydroxyguanosine (8OHG), and oxidized protein, nitrotyrosine, in the cytoplasm of cerebral neurons in DS with the levels of nucleic acid and protein oxidation paralleling each other. Relative density measurements of neuronal 8OHG immunoreactivity showed that there was a significant increase (p < 0.02) in DS (n = 22, ages 0.3-65 yr) compared with age-matched controls (n = 10, ages 0.3-64 yr). As a function of age, 8OHG immunoreactivity increased significantly in the teens and twenties (p < 0.04), while Aβ burden only increased after age 30 (p < 0.0001). In 9 cases of DS bearing Aβ deposition, the extent of deposits of Aβ ending at amino acid 42 (Aβ42) was actually associated with a decrease in relative 8OHG (r = -0.79, p < 0.015) while Aβ40 was not. These findings suggest that in brains of patients with DS, increased levels of oxidative damage occur prior to the onset of Aβ deposition.

Original languageEnglish (US)
Pages (from-to)1011-1017
Number of pages7
JournalJournal of Neuropathology and Experimental Neurology
Volume59
Issue number11
DOIs
StatePublished - Jan 1 2000
Externally publishedYes

Keywords

  • 8-hydroxyguanosine
  • Alzheimer disease
  • Amyloid-β
  • Down syndrome
  • Nitric oxide
  • Nitrotyrosine
  • Oxidative damage

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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