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The Journal of Neuroscience, October 1, 2003, 23(26):8967-8977

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Development/Plasticity/Repair
Glutamate and Amyloid -Protein Rapidly Inhibit Fast Axonal Transport in Cultured Rat Hippocampal Neurons by Different Mechanisms

Hiromi Hiruma,¹ Takashi Katakura,¹ Sanae Takahashi,¹ Takafumi Ichikawa,² and Tadashi Kawakami¹

Departments of ¹Physiology and ²Biochemistry, Kitasato University School of Medicine, Sagamihara 228-8555, Japan

Impairment of axonal transport leads to neurodegeneration and synapse loss. Glutamate and amyloid -protein (A) have critical roles in the pathogenesis of Alzheimer's disease (AD). Here we show that both agents rapidly inhibit fast axonal transport in cultured rat hippocampal neurons. The effect of glutamate (100 µM), but not of A_25-35 (20 µM), was reversible, was mimicked by NMDA or AMPA, and was blocked by NMDA and AMPA antagonists and by removal of extracellular Ca²⁺. The effect of A_25-35 was progressive and irreversible, was prevented by the actin-depolymerizing agent latrunculin B, and was mimicked by the actin-polymerizing agent jasplakinolide. A_25-35 induced intracellular actin aggregation, which was prevented by latrunculin B. A_31-35 but not A_15-20 exerted effects similar to those of A_25-35. Full-length A_1-42 incubated for 7 d, which specifically contained 30-100 kDa molecular weight assemblies, also caused an inhibition of axonal transport associated with intracellular actin aggregation, whereas freshly dissolved A_1-40, incubated A_1-40, and fresh A_1-42 had no effect. These results suggest that glutamate inhibits axonal transport via activation of NMDA and AMPA receptors and Ca²⁺ influx, whereas A exerts its inhibitory effect via actin polymerization and aggregation. The ability of A to inhibit axonal transport seems to require active amino acid residues, which is probably present in the 31-35 sequence. Full-length A may be effective when it represents a structure in which these active residues can access the cell membrane. Our results may provide insight into the early pathogenetic mechanisms of AD.

Key words: axonal transport; glutamate; amyloid -protein; actin; Ca²⁺; cultured hippocampal neurons

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Received Feb 11, 2003; revised August 11, 2003; accepted August 14, 2003.

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