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P3–366: The complexation of amyloid–β with heme forms a peroxidase: Mechanism of neurotoxicity in Alzheimer's disease
Author(s) -
Atamna Hani,
Boyle Kathleen
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1636
Subject(s) - heme , peroxidase , oxidative stress , chemistry , biochemistry , neurotoxicity , neurodegeneration , amyloid (mycology) , amyloid precursor protein , oxidative phosphorylation , alzheimer's disease , microbiology and biotechnology , enzyme , biology , toxicity , medicine , disease , inorganic chemistry , organic chemistry
lieved to play a major role in acetaldehyde detoxification in the ethanol metabolism. The alcohol sensitivity is associated with a mutant allele of the ALDH2 gene (ALDH2*2), which results in a substitution of Glu 487 to Lys, acting in a dominant negative fashion. Our molecular epidemiologic analysis has shown the association of Alzheimer’s disease (AD) with ALDH2*2 allele. The concentration of lipid peroxides (LPO) was significantly higher in defective ALDH2 females than nondefective ones, suggesting that ALDH2 functions as a protector against oxidative stress. Indeed, ALDH2 detoxifies reactive aldehydes, such as 4-hydroxyl-2-nonenal (4-HNE), that are derived from LPO. Objective(s): To clarify a role of ALDH2-deficiency in age-associated neurodegenerative diseases such as AD, we examined physiological changes and learning and memory impairments that occur in transgenic mice expressing ALDH2*2 in the brain. Methods: We constructed transgenic mice by introducing the mouse-version of the ALDH2*2 gene, and named the resultant mice DAL (Dominant negative of ALDH2) mice. Results: Female DAL mice exhibited no particular abnormality on physical examinations compared with control C57BL/6 mice when observed until 18 months after birth. However, primary cultured neocortical cells from DAL mouse embryos exhibited increase in vulnerability to 4-HNE. Therefore, autopsy of the brain was performed in 6-month-old mice, but no difference compared with the brain of control C57BL/6 mice was noted, whereas in 18-month-old DAL mice, signs of neurodegeneration such as atrophy of the hippocampus and associated loss of pyramidal cells and activation of glial cells were observed. These changes were sporadically observed from 12-month-old and increased with aging. The old-aged DAL mice also developed prominent deficits in special memory in the Morris water-maze test, whereas young DAL mice (6-month) looked normal. Accumulation of oxidative stress in the brain of DAL mice will be further discussed. Conclusions: Brain degeneration and decline in spatial cognitive ability in DAL mice are considered to be due to decrease in resistance to oxidative stress. Analysis of these mice will clarify the relationship between lesions characteristic of AD and oxidative stress.