| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2004: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
The 26-28 months old V642I-APP knock-in heterozygous mutant mice, a novel familial Alzheimer's disease (AD) model (Eur J Neurosci.19:2826), showed elevated Aβ1-42/Aβ1-40 ratio in cerebrum homogenates, which is typically observed in patients diagnosed as AD. Performance for the behavioral tests related to memory and learning functions was significantly deteriorated at this age, without apparent formation of senile plaques, neurofibrillary tangles, or massive loss of neurons in cerebrum. Aged heterozygous mutants may therefore reflect the early pathogenetic molecular processes of human AD. Based upon this hypothesis, the quantitative and/or qualitative alteration in gene expression profiles in cerebrum of the aged mice was investigated. Differential display (DD) analysis of the pooled brain samples (four groups : n=5 for mutants and wild types, male and female) detected 207 DD-PCR products, among which 18 showed altered amplification. Differential expression of the 3 independent candidates was confirmed by semi-quantitative PCR analysis and Northern analysis. Analysis of the same brain samples by cDNA subtraction revealed a series of differentially expressed gene candidates, with 6 of which the real-time PCR quantitative analysis confirmed the alteration in gene expression in a V642I-APP mutation-dependent manner. These genes were additionally analyzed for the two sibling pairs of 29 month-old V642I-APP heterozygous mutants and wild type littermates by real-time PCR, which confirmed the nature of the differential expression particularly in cerebral cortex.
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