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In vivo oxidative stress in brain of Alzheimer disease transgenic mice: Requirement for methionine 35 in amyloid beta-peptide of APP.

ABSTRACT: Numerous studies have demonstrated oxidative damage in the central nervous system in subjects with Alzheimer disease and in animal models of this dementing disorder. In this study, we show that transgenic mice modeling Alzheimer disease-PDAPP mice with Swedish and Indiana mutations in the human amyloid precursor protein (APP)-develop oxidative damage in brain, including elevated levels of protein oxidation (indexed by protein carbonyls and 3-nitrotyrosine) and lipid peroxidation (indexed by protein-bound 4-hydroxy-2-nonenal). This oxidative damage requires the presence of a single methionine residue at position 35 of the amyloid beta-peptide (Abeta), because all indices of oxidative damage in brain were completely prevented in genetically and age-matched PDAPP mice with an M631L mutation in APP. No significant differences in the levels of APP, Abeta(1-42), and Abeta(1-40) or in the ratio Abeta(1-42)/Abeta(1-40) were found, suggesting that the loss of oxidative stress in vivo in the brain of PDAPP(M631L) mice results solely from the mutation of the Met35 residue to Leu in the Abeta peptide. However, a marked reduction in Abeta-immunoreactive plaques was observed in the M631L mice, which instead displayed small punctate areas of nonplaque immunoreactivity and a microglial response. In contrast to the requirement for Met at residue 35 of the Abeta sequence (M631 of APP) for oxidative damage, indices of spatial learning and memory were not significantly improved by the M631L substitution. Furthermore, a genetically matched line with a different mutation-PDAPP(D664A)-showed the reverse: no reduction in oxidative damage but marked improvement in memory. This is the first in vivo study to demonstrate the requirement for Abeta residue Met35 for oxidative stress in the brain of a mammalian model of Alzheimer disease. However, in this specific transgenic mouse model of AD, oxidative stress is neither required nor sufficient for memory abnormalities.

SUBMITTER: Butterfield DA

PROVIDER: S-EPMC2818480 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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In vivo oxidative stress in brain of Alzheimer disease transgenic mice: Requirement for methionine 35 in amyloid beta-peptide of APP.

Butterfield D Allan DA Galvan Veronica V Lange Miranda Bader MB Tang Huidong H Sowell Renã A RA Spilman Patricia P Fombonne Joanna J Gorostiza Olivia O Zhang Junli J Sultana Rukhsana R Bredesen Dale E DE

Free radical biology & medicine 20091023 1

Numerous studies have demonstrated oxidative damage in the central nervous system in subjects with Alzheimer disease and in animal models of this dementing disorder. In this study, we show that transgenic mice modeling Alzheimer disease-PDAPP mice with Swedish and Indiana mutations in the human amyloid precursor protein (APP)-develop oxidative damage in brain, including elevated levels of protein oxidation (indexed by protein carbonyls and 3-nitrotyrosine) and lipid peroxidation (indexed by prot ...[more]

PMID: 19854267

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Project description:Positron emission tomography (PET) used for visualizing amyloid-? (A?) pathology has become an important tool for specific clinical diagnosis of Alzheimer's disease (AD). However, all available amyloid PET radioligands, such as [11C]PiB, reflect levels of insoluble A? plaques, but do not capture soluble and protofibrillar A? forms. When measured with current PET ligands, the plaque load appears to be fairly static during clinical stages of AD, and may not be affected by A? reducing treatments. The aim of the present study was to investigate if a novel PET radioligand, based on an antibody directed towards soluble aggregates of A?, could be used to detect changes in A? levels during disease progression and after treatment with a ?-secretase (BACE-1) inhibitor. Methods: One set of transgenic mice (tg-ArcSwe, model of A? pathology) aged between 7 and 16 months were PET scanned with the A? protofibril selective radioligand [124I]RmAb158-scFv8D3 to follow progression of A? pathology in the brain. A second set of tg-ArcSwe mice, aged 10 months, were treated with BACE-1 inhibitor NB-360 for 3 months and compared to an untreated control group. A set of 10 months old tg-ArcSwe mice also underwent PET scanning, acting as a baseline group. Brain tissue was isolated after PET to determine levels of A? by ELISA and immunohistochemistry. Results: Concentration of [124I]RmAb158-scFv8D3 in tg-ArcSwe mice, measured in vivo with PET, increased with age and corresponded well with ex vivo autoradiography and A? immunohistochemistry. Tg-ArcSwe mice treated with NB-360 showed significantly lower in vivo PET signals than untreated animals, and were similar to the baseline 10 month old animals. The decreased [124I]RmAb158-scFv8D3 concentrations in NB-360 treated mice, quantified with PET, corresponded well with decreased A? levels measured in post mortem brain. Conclusion: A number of treatments for AD are currently studied in phase 2 and 3 clinical trials but there are limited possibilities to study their effects on the important, non-fibrillar A? forms in vivo. This study demonstrates the ability of the A? protofibril selective radioligand [124I]RmAb158-scFv8D3 to follow disease progression and detect treatment effects with PET imaging in tg-ArcSwe mice.

Dataset Information

In vivo oxidative stress in brain of Alzheimer disease transgenic mice: Requirement for methionine 35 in amyloid beta-peptide of APP.

Publications

In vivo oxidative stress in brain of Alzheimer disease transgenic mice: Requirement for methionine 35 in amyloid beta-peptide of APP.

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