| Budget Amount *help |
¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2003: ¥700,000 (Direct Cost: ¥700,000)
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| Research Abstract |
Impairment of axonal transport leads to neurodegeneration and synapse loss. β-Amyloid (Aβ) has critical roles in the pathogenesis of Alzheimer's disease. The present study demonstrated that Aβ rapidly inhibited fast axonal transport in cultured rat hippocampal neurons. The effect of Aβ was progressive and irreversible, was prevented by the actin-depolymerizing agent latrunculin B, and was mimicked by the actin-polymerizing agent jasplakinolide. Aβ induced intracellular actin aggregation, which was prevented by latrunculin B. Aβ fragments Aβ_<31-35> and Aβ_<25-35> exerted the aggregation of action filaments and the inhibition of axonal transport, but Aβ_<15-20> had no effect. Aβ_<1-42> incubated for 7 days, which specifically contained 30-100 kDa molecular weight assemblies, also caused an inhibition of axonal transport associated with intracellular actin aggregation, whereas freshly dissolved Aβ_<1-40>, incubated Aβ_<1-40>, and fresh Aβ_<1-42> had no effect. These results suggest that AB inhibits axonal transport via actin polymerization and aggregation. The ability of Aβ to inhibit axonal transport seems to require active amino acid residues, which is probably present in the 31-35 sequence. Full-length Aβ may be effective when it represents a structure where these active residues can access the cell membrane. The present results may provide insight into the early pathogenetic mechanisms of Alzheimer's disease.
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