Budget Amount *help |
¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000)
Fiscal Year 2011: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2010: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Fiscal Year 2009: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
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Research Abstract |
Age-related memory impairment(AMI) is a debilitating consequence of brain aging that can be suppressed in Drosophila by reducing PKA activity. However, the molecular mechanisms underlying AMI remain unclear. Using proteome analyses of wild-type and PKA mutants, we identified an AMI-associated increase in the activity of Drosophila pyruvate carboxylase(dPC), a mitochondrial anaplerotic enzyme. Genetic and biochemical data demonstrate that age-related increases in glial dPC cause AMI and that PKA mutations suppress AMI by reducing dPC activity. Although increased oxidative stress has been proposed to cause AMI, increases in dPC activity are not associated with increased oxidative stress. Strikingly, although the production of D-serine, a glia-derived NMDA receptor agonist, decreases in aged flies, this decrease is suppressed by dPC mutations and AMI is ameliorated by feeding flies D-serine. We propose a novel oxidative stress-independent AMI signaling pathway in which age-related increases in glial mitochondrial dPC activity cause AMI by reducing D-serine production.
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