Hydroxynonenal-generated crosslinking fluorophore accumulation in Alzheimer disease reveals a dichotomy of protein turnover

Xiongwei Zhu, Rudy J. Castellani, Paula I. Moreira, Gjumrakch Aliev, Justin C. Shenk, Sandra L. Siedlak, Peggy L.R. Harris, Hisashi Fujioka, Lawrence M. Sayre, Pamela A. Szweda, Luke I. Szweda, Mark A. Smith, George Perry

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


Lipid peroxidation generates reactive aldehydes, most notably hydroxynonenal (HNE), which covalently bind amino acid residue side chains leading to protein inactivation and insolubility. Specific adducts of lipid peroxidation have been demonstrated in intimate association with the pathological lesions of Alzheimer disease (AD), suggesting that oxidative stress is a major component of AD pathogenesis. Some HNE-protein products result in protein crosslinking through a fluorescent compound similar to lipofuscin, linking lipid peroxidation and the lipofuscin accumulation that commonly occurs in post-mitotic cells such as neurons. In this study, brain tissue from AD and control patients was examined by immunocytochemistry and immunoelectron microscopy for evidence of HNE-crosslinking modifications of the type that should accumulate in the lipofuscin pathway. Strong labeling of granulovacuolar degeneration (GVD) and Hirano bodies was noted but lipofuscin did not contain this specific HNE-fluorophore. These findings directly implicate lipid crosslinking peroxidation products as accumulating not in the lesions or the lipofuscin pathways, but instead in a distinct pathway, GVD, that accumulates cytosolic proteins.

Original languageEnglish (US)
Pages (from-to)699-704
Number of pages6
JournalFree Radical Biology and Medicine
Issue number3
StatePublished - Feb 1 2012


  • Hirano body
  • fluorophore
  • granulovacuolar degeneration
  • hydroxynonenal
  • lipid peroxidation
  • lipofuscin
  • oxidative stress
  • protein cross-linking

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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