Lipids

, Volume 34, Issue 12, pp 1273–1280

Cerebrospinal fluid lipoproteins are more vulnerable to oxidation in Alzheimer’s disease and are neurotoxic when oxidized ex vivo

  • Casey N. Bassett
  • M. Diana Neely
  • Kathrin R. Sidell
  • William R. Markesbery
  • Larry L. Switt
  • Thomas J. Montine
Article

DOI: 10.1007/s11745-999-0478-1

Cite this article as:
Bassett, C.N., Neely, M.D., Sidell, K.R. et al. Lipids (1999) 34: 1273. doi:10.1007/s11745-999-0478-1

Abstract

Brain regional oxidative damage is thought to be a central mechanism in the pathogenesis of Alzheimer’s disease (AD). Recent studies of cerebrospinal fluid (CSF) have suggested that increased lipid peroxidation of CSF and CSF lipoproteins also may occur in AD patients. In the present study, we determined the susceptibility of human CSF to ex vivo lipid peroxidation and tested the hypothesis that oxidized CSF lipoproteins may be neurotoxic. Whole CSF or a CSF lipoprotein fraction (d<1.210 g/mL) was oxidized with 2,2′-azobis(2-amidino-propane)dihydrochloride (AAPH), a hydrophilic free-radical generator. Kinetics of CSF lipid peroxidation were followed by a standard fluorescence product accumulation assay. Oxidation of AD CSF yielded significantly shorter fluorescent lag times than controls, indicating reduced antioxidant capacity. Electrophoretic mobilities of CSF apolipoproteins were specifically reduced upon oxidation of CSF with AAPH, suggesting that lipoproteins are primary targets of CSF lipid peroxidation. Cultured neuronal cells were exposed to physiological concentrations of isolated CSF lipoproteins oxidized with increasing concentrations of AAPH; the resulting neurotoxicity showed a significant linear AAPH concentration-response relationship. These results suggest that oxidized CSF lipoproteins may contribute to the pathogenesis of neurodegeneration in AD.

Abbreviations

AAPH

2,2′-azobis(2-amidinopropane)dihydrochloride

AD

Alzheimer’s disease

ANOVA

analysis of variance

apo

apolipoprotein

APOE

human apolipoprotein E gene

APOE4

ε4 alleles of APOE

BCA

bicinchoninic acid

CNS

central nervous system

CSF

cerebrospinal fluid

Dil

1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate

LDL

low density lipoprotein

PBS

phosphate-buffered saline at pH 7.4

RFU

relative fluorescence units

Copyright information

© AOCS Press 1999

Authors and Affiliations

  • Casey N. Bassett
    • 1
  • M. Diana Neely
    • 1
  • Kathrin R. Sidell
    • 3
  • William R. Markesbery
    • 4
  • Larry L. Switt
    • 1
  • Thomas J. Montine
    • 1
    • 2
    • 3
  1. 1.Department of PathologyVanderbilt University Medical CenterNashville, Tennessee
  2. 2.Department of Pharmacology and the Vanderbilt University Medical CenterNashville, Tennessee
  3. 3.Department of Center for Molecular NeurosciencesVanderbilt University Medical CenterNashville, Tennessee
  4. 4.Sanders-Brown Center on Aging and the Departments of Pathology and NeurologyUniversity of Kentucky Medical CenterLexington

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