Analyses on oxidative stress and amyloid β protein in brains of mice with modified apolipoprotein E gene

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Alzheimer's disease (AD) is characterized by the extensive deposition of amyloid β protein (Aβ) in brain cortex. Aβ generation reveals to be induced by oxidative stress, and Aβ is reported to evoke oxidative stress through generating reactive oxygen species, etc. In addition, apolipoprotein E (apoE)-ε4 genotype, one of the most powerful risk factors for all types of AD, has been elucidated in vitro to show less anti-oxidant effect than apoE-ε3 genotype. We have already shown that temporal cortices from patients with AD carrying apoE-ε4 homotypes contained more thiobarbituric acid-reactive substances (TBARS) than those carrying ε3 homotypes, suggesting that the lower antioxidant activity of apoe-E4 could contribute to its association with AD.We first measured TBARS in brains from apoE-knockout and wild type mice, elucidating that the former showed significantly more TBARS than the latter, suggesting antioxidant activities of apoE. We measured then TBARS in brains from human apoE3-knockin and apoE4-knockin mice, revealing that no differences in whole brain homogenates, but more TBARS with no significance in purified lipid raft fractions from apoE4-knockin than those from apoE3-knockin mice.We further investigated effects of chronic hypoperfusion on rat brains by bilateral carotid artery occlusions (BCAO). Both Aβ40 and Aβ42 were more increased in BCAO rat brains than those from sham-operated rats employed as controls. Immunocytochemical studies showed more expression of BACE1 than controls. Taking all these findings together in consideration, chronic hypoperfusion could induce BACE1 expression facilitating AD-deposion, the mechanism of which might be partly by evoking oxidative stress.Further studies are necessary to clarify the pathomechanism by which apoE-64 could be risk for AD and its relations to oxidative stress and Aβ generation.