Reduced neuronal expression of synaptic transmission modulator HNK-1/neural cell adhesion molecule as a potential consequence of amyloid β-mediated oxidative stress: A proteomic approach

Stefani N. Thomas, Brian A. Soreghan, Mihaela Nistor, Floyd Sarsoza, Elizabeth Head, Austin J. Yang

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Oxidative stress imparted by reactive oxygen species (ROS) is implicated in the pathogenesis of Alzheimer's disease (AD). Given that amyloid β (Aβ) itself generates ROS that can directly damage proteins, elucidating the functional consequences of protein oxidation can enhance our understanding of the process of Aβ-mediated neurodegeneration. In this study, we employed a biocytin hydrazide/streptavidin affinity purification methodology followed by two-dimensional liquid chromatography tandem mass spectrometry coupled with SEQUEST bioinformatics technology, to identify the targets of Aβ-induced oxidative stress in cultured primary cortical mouse neurons. The Golgi-resident enzyme glucuronyltransferase (GlcAT-P) was a carbonylated target that we investigated further owing to its involvement in the biosynthesis of HNK-1, a carbohydrate epitope expressed on cell adhesion molecules and implicated in modulating the effectiveness of synaptic transmission in the brain. We found that increasing amounts of Aβ, added exogenously to the culture media of primary cortical neurons, significantly decreased HNK-1 expression. Moreover, in vivo, HNK-1 immunoreactivity was decreased in brain tissue of a transgenic mouse model of AD. We conclude that a potential consequence of Aβ-mediated oxidation of GlcAT-P is impairment of its enzymatic function, thereby disrupting HNK-1 biosynthesis and possibly adversely affecting synaptic plasticity. Considering that AD is partly characterized by progressive memory impairment and disordered cognitive function, the data from our in vitro studies can be reconciled with results from in vivo studies that have demonstrated that HNK-1 modulates synaptic plasticity and is critically involved in memory consolidation.

Original languageEnglish (US)
Pages (from-to)705-717
Number of pages13
JournalJournal of Neurochemistry
Volume92
Issue number4
DOIs
StatePublished - Feb 1 2005
Externally publishedYes

    Fingerprint

Keywords

  • Amyloid-β
  • Glucuronyltransferase
  • Human Natural Killer (HNK-1)
  • Liquid chromatography tandem mass spectrometry
  • Oxidative stress

Cite this