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J Neurosci. 2003 Oct 1;23(26):8967-77.

Glutamate and amyloid beta-protein rapidly inhibit fast axonal transport in cultured rat hippocampal neurons by different mechanisms.

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  • 1Department of Physiology, Kitasato University School of Medicine, Sagamihara 228-8555, Japan. hiruma@med.kitasato-u.ac.jp

Abstract

Impairment of axonal transport leads to neurodegeneration and synapse loss. Glutamate and amyloid beta-protein (Abeta) 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 microm), but not of Abeta25-35 (20 microm), 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 Abeta25-35 was progressive and irreversible, was prevented by the actin-depolymerizing agent latrunculin B, and was mimicked by the actin-polymerizing agent jasplakinolide. Abeta25-35 induced intracellular actin aggregation, which was prevented by latrunculin B. Abeta31-35 but not Abeta15-20 exerted effects similar to those of Abeta25-35. Full-length Abeta1-42 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 Abeta1-40, incubated Abeta1-40, and fresh Abeta1-42 had no effect. These results suggest that glutamate inhibits axonal transport via activation of NMDA and AMPA receptors and Ca2+ influx, whereas Abeta exerts its inhibitory effect via actin polymerization and aggregation. The ability of Abeta to inhibit axonal transport seems to require active amino acid residues, which is probably present in the 31-35 sequence. Full-length Abeta 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.

PMID:
14523099
[PubMed - indexed for MEDLINE]
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