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

Casey Bassett, M. Diana Neely, Kathrin R. Sidell, William R. Markesbery, Larry L. Swift, Thomas J. Montine

Research output: Contribution to journalArticle

50 Citations (Scopus)

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-amidinopropane)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.

Original languageEnglish (US)
Pages (from-to)1273-1280
Number of pages8
JournalLipids
Volume34
Issue number12
DOIs
StatePublished - Jan 1 1999
Externally publishedYes

Fingerprint

Cerebrospinal fluid
Lipoproteins
Cerebrospinal Fluid
Alzheimer Disease
Oxidation
Lipid Peroxidation
Lipids
Electrophoretic mobility
Apolipoproteins

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Cell Biology

Cite this

Cerebrospinal fluid lipoproteins are more vulnerable to oxidation in Alzheimer's disease and are neurotoxic when oxidized ex vivo. / Bassett, Casey; Neely, M. Diana; Sidell, Kathrin R.; Markesbery, William R.; Swift, Larry L.; Montine, Thomas J.

In: Lipids, Vol. 34, No. 12, 01.01.1999, p. 1273-1280.

Research output: Contribution to journalArticle

Bassett, Casey ; Neely, M. Diana ; Sidell, Kathrin R. ; Markesbery, William R. ; Swift, Larry L. ; Montine, Thomas J. / Cerebrospinal fluid lipoproteins are more vulnerable to oxidation in Alzheimer's disease and are neurotoxic when oxidized ex vivo. In: Lipids. 1999 ; Vol. 34, No. 12. pp. 1273-1280.
@article{a5e884c8c20b4f4c81239e104c7f6caa,
title = "Cerebrospinal fluid lipoproteins are more vulnerable to oxidation in Alzheimer's disease and are neurotoxic when oxidized ex vivo",
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-amidinopropane)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.",
author = "Casey Bassett and Neely, {M. Diana} and Sidell, {Kathrin R.} and Markesbery, {William R.} and Swift, {Larry L.} and Montine, {Thomas J.}",
year = "1999",
month = "1",
day = "1",
doi = "10.1007/s11745-999-0478-1",
language = "English (US)",
volume = "34",
pages = "1273--1280",
journal = "Lipids",
issn = "0024-4201",
publisher = "Springer Verlag",
number = "12",

}

TY - JOUR

T1 - Cerebrospinal fluid lipoproteins are more vulnerable to oxidation in Alzheimer's disease and are neurotoxic when oxidized ex vivo

AU - Bassett, Casey

AU - Neely, M. Diana

AU - Sidell, Kathrin R.

AU - Markesbery, William R.

AU - Swift, Larry L.

AU - Montine, Thomas J.

PY - 1999/1/1

Y1 - 1999/1/1

N2 - 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-amidinopropane)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.

AB - 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-amidinopropane)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.

UR - http://www.scopus.com/inward/record.url?scp=0033374599&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033374599&partnerID=8YFLogxK

U2 - 10.1007/s11745-999-0478-1

DO - 10.1007/s11745-999-0478-1

M3 - Article

VL - 34

SP - 1273

EP - 1280

JO - Lipids

JF - Lipids

SN - 0024-4201

IS - 12

ER -