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Aging, gender and APOE isotype modulate metabolism of Alzheimer's Aβ peptides and F 2 ‐isoprostanes in the absence of detectable amyloid deposits
Author(s) -
Yao Jun,
Petanceska Suzana S.,
Montine Thomas J.,
Holtzman David M.,
Schmidt Stephen D.,
Parker Carolyn A.,
Callahan Michael J.,
Lipinski William J.,
Bisgaier Charles L.,
Turner Brian A.,
Nixon Ralph A.,
Martins Ralph N.,
Ouimet Charles,
Smith Jonathan D.,
Davies Peter,
Laska Eugene,
Ehrlich Michelle E.,
Walker Lary C.,
Mathews Paul M.,
Gandy Sam
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02532.x
Subject(s) - apolipoprotein e , genetically modified mouse , endocrinology , medicine , amyloid (mycology) , biology , transgene , human brain , genotype , amyloidosis , endogeny , alzheimer's disease , disease , genetics , neuroscience , gene , botany
Aging and apolipoprotein E ( APOE ) isoform are among the most consistent risks for the development of Alzheimer's disease (AD). Metabolic factors that modulate risk have been elusive, though oxidative reactions and their by‐products have been implicated in human AD and in transgenic mice with overt histological amyloidosis. We investigated the relationship between the levels of endogenous murine amyloid β (Aβ) peptides and the levels of a marker of oxidation in mice that never develop histological amyloidosis [i.e. APOE knockout (KO) mice with or without transgenic human APOE ɛ3 or human APOE ɛ4 alleles]. Aging‐, gender‐, and APOE ‐genotype‐dependent changes were observed for endogenous mouse brain Aβ40 and Aβ42 peptides. Levels of the oxidized lipid F 2 ‐isoprostane (F 2 ‐ iso Ps) in the brains of the same animals as those used for the Aβ analyses revealed aging‐ and gender‐dependent changes in APOE KO and in human APOE ɛ4 transgenic KO mice. Human APOE ɛ3 transgenic KO mice did not exhibit aging‐ or gender‐dependent increases in F 2 ‐ iso Ps. In general, the changes in the levels of brain F 2 ‐ iso Ps in mice according to age, gender, and APOE genotype mirrored the changes in brain Aβ levels, which, in turn, paralleled known trends in the risk for human AD. These data indicate that there exists an aging‐dependent, APOE ‐genotype‐sensitive rise in murine brain Aβ levels despite the apparent inability of the peptide to form histologically detectable amyloid. Human APOE ɛ3, but not human APOE ɛ4, can apparently prevent the aging‐dependent rise in murine brain Aβ levels, consistent with the relative risk for AD associated with these genotypes. The fidelity of the brain Aβ/F 2 ‐ iso P relationship across multiple relevant variables supports the hypothesis that oxidized lipids play a role in AD pathogenesis, as has been suggested by recent evidence that F 2 ‐ iso Ps can stimulate Aβ generation and aggregation.