Vulnerability of synaptosomes from apoE knock-out mice to structural and oxidative modifications induced by A beta(1-40): implications for Alzheimer's disease.
Apolipoprotein E (apoE) plays an important role in the response to central nervous system injury. The e4 allele of apoE and amyloid beta-peptide (Abeta) are associated with Alzheimer's disease (AD) and may be central to the pathogenesis of this disorder. Recent studies demonstrate evidence for neurodegeneration and increased lipid peroxidation in transgenic mice lacking apoE (KO). In the current study, synaptosomes were prepared from apoE KO mice to determine the role of apoE in synaptic membrane structure and to determine susceptibility to oxidative damage by Abeta(1-40). ApoE KO mice exhibited structural modifications to lipid and protein components of synaptosomal membranes as determined by electron paramagnetic resonance in conjunction with lipid- and protein- specific spin labels. Incubation with 5 microM Abeta(1-40) resulted in more severe oxidative modifications to proteins and lipids in apoE KO synaptosomes as measured by protein carbonyls, an index of protein oxidation, and TBARs and protein-bound 4-hydroxynonenal (HNE), markers of lipid oxidation. Together, these data support a role for apoE in the modulation of oxidative injury and in the maintenance of synaptic integrity and are discussed with reference to alterations in AD brain.
Lauderback
C M
CM
Department of Chemistry, Center of Membrane Sciences, and Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky 40506, USA.
Hackett
J M
JM
Keller
J N
JN
Varadarajan
S
S
Szweda
L
L
Kindy
M
M
Markesbery
W R
WR
Butterfield
D A
DA
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics*; D006861:Hydrogen Peroxide / Q000378:metabolism; D015227:Lipid Peroxidation / Q000235:genetics; D008297:Male; D008560:Membrane Fluidity / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000494:pharmacology*; D013574:Synaptosomes / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D010446:Peptide Fragments; D017392:Thiobarbituric Acid Reactive Substances; C078592:amyloid beta-protein (1-40); D006861:Hydrogen Peroxide