|Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥2,600,000 (Direct Cost: ¥2,600,000)
Specific Aim : In the brain, apolipoprotein E(ApoE) is secreted from astrocytes and microglias, and plays important roles in lipid transportation. Furthermore, ApoE may protect neurons from many kinds of insults. Our aim is to elucidate the molecular mechanisms where ApoE protect neurons.
Results : When primary neurons were cultured under serum-free conditions, they underwent cell deaths. When ApoE3 was added to the serum-free medium, their deaths were significantly inhibited, On the other hand, when ApoE4 was added to the serum-free medium, their deaths were significantly promoted. Tau protein in the neurons were significantly phosphorylated, then. To substantiate this concept, we mated Reelin-deficient mice to ApoE-deficient mice and found that in the absence of Reelin, tau-phosphorylation in neurons of the brain increased as the amount of ApoE decreased. Paralleling the change in tau-phosphorylation levels, we found that GSK-3β activity increased in Reelin-deficient mice and further increased in mice lacking both Reelin and ApoE. CDK-5 activity was similar in mice lacking Reelin, ApoE, or both. GSK-3β and CDK-5 activity increased in Dab1-deficient mice, independent of ApoE levels. Further supporting the idea that increased tau-phosphorylation results primarily from increased kinase activity, the activity of 2 phosphatases were similar in all conditions tested.
Conclusions : These data support a novel, ligand-mediated signal transduction cascade-initiated by the assembly of a RAD complex that suppresses kinase activity and controls tau-phosphorylation.