Aging, gender and APOE isotype modulate metabolism of Alzheimer's Aβ peptides and F₂‐isoprostanes in the absence of detectable amyloid deposits

Abstract

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 b (Ab) 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 e3 or human APOE e4 alleles]. Aging-, gender-, and APOE-genotypedependent changes were observed for endogenous mouse brain Ab40 and Ab42 peptides. Levels of the oxidized lipid F 2 -isoprostane (F 2 -isoPs) in the brains of the same animals as those used for the Ab analyses revealed aging-and genderdependent changes in APOE KO and in human APOE e4 transgenic KO mice. Human APOE e3 transgenic KO mice did not exhibit aging-or gender-dependent increases in F 2 -isoPs. In general, the changes in the levels of brain F 2 -isoPs in mice according to age, gender, and APOE genotype mirrored the changes in brain Ab 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 Ab levels despite the apparent inability of the peptide to form histologically detectable amyloid. Human APOE e3, but not human APOE e4, can apparently prevent the aging-dependent rise in murine brain Ab levels, consistent with the relative risk for AD associated with these genotypes. The fidelity of the brain Ab/F 2 -isoP relationship across multiple relevant variables supports the hypothesis that oxidized lipids

The role of cerebral amyloid accumulation in common forms of Alzheimer disease

“…We recently demonstrated that, unlike human ε3, human ε4 is associated with elevated levels of endogenous murine brain Aβ as a function of aging and gender, even in mice that will therefore never develop cerebral amyloidosis. These data support the conclusion that there exists an effect of ε4 on Aβ upstream of fibrillogenesis (41).…”

“…This is an important point because human (but not murine) Aβ is reported to be a pro-oxidant (49). We were able to dissociate the isoprostane elevation from the formation of histological amyloid by using mice bearing only endogenous murine APP and Aβ (41). Thus, plaque formation is not a prerequisite for elevation of brain isoprostane levels.…”

Thiamine deficiency induces oxidative stress and exacerbates the plaque pathology in Alzheimer's mouse model

“…In the studies by Li et al [37], no difference in plaque load was observed between males and females of the same transgenic mice (Tg19959 mice). Plaque load in Tg2576 mice does not vary with gender either, although males are more sensitive to alterations in APOE genotype [56]. Other studies suggest sex differences in Tg mice carrying APP with Swedish and the presenilin-1 A246 mutation.…”

Impact of apoE genotype on oxidative stress, inflammation and disease risk

“…In mice, it has been shown that Ab induction of oxidation in isolated synaptosomes leads to increased reactive oxygen species formation in mice expressing apoE4 relative to apoE3 [49]. Furthermore, Yao et al [50] found increased levels of F 2 -isoprostanes in brains of apoE4 male mice, but found no genotype differences in female mice. More recently a new body of evidence has emerged, from both human observational and cell culture studies, indicating a role of apoE genotype on oxidative status measures, relevant to the progression of CVD.…”