Glutamate and Amyloid β-Protein Rapidly Inhibit Fast Axonal Transport in Cultured Rat Hippocampal Neurons by Different Mechanisms

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Abstract
Impairment of axonal transport leads to neurodegeneration and synapse loss. Glutamate and amyloid β-protein (Aβ) 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 Aβ25-35(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 Aβ25-35was progressive and irreversible, was prevented by the actin-depolymerizing agent latrunculin B, and was mimicked by the actin-polymerizing agent jasplakinolide. Aβ25-35induced intracellular actin aggregation, which was prevented by latrunculin B. Aβ31-35but not Aβ15-20exerted effects similar to those of Aβ25-35. Full-length Aβ1-42incubated 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 Aβ1-40, incubated Aβ1-40, and fresh Aβ1-42had no effect. These results suggest that glutamate inhibits axonal transport via activation of NMDA and AMPA receptors and Ca2+influx, whereas Aβ exerts its inhibitory effect 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 in which these active residues can access the cell membrane. Our results may provide insight into the early pathogenetic mechanisms of AD.