| First Author | Lee SJ | Year | 2015 |
| Journal | Mol Brain | Volume | 8 |
| Issue | 1 | Pages | 84 |
| PubMed ID | 26637294 | Mgi Jnum | J:316466 |
| Mgi Id | MGI:6837776 | Doi | 10.1186/s13041-015-0173-3 |
| Citation | Lee SJ, et al. (2015) Metallothionein-3 modulates the amyloid beta endocytosis of astrocytes through its effects on actin polymerization. Mol Brain 8(1):84 |
| abstractText | BACKGROUND: Astrocytes may play important roles in the pathogenesis of Alzheimer's disease (AD) by clearing extracellular amyloid beta (Abeta) through endocytosis and degradation. We recently showed that metallothionein 3 (Mt3), a zinc-binding metallothionein that is enriched in the central nervous system, contributes to actin polymerization in astrocytes. Because actin is likely involved in the endocytosis of Abeta, we investigated the possible role of Mt3 in Abeta endocytosis by cortical astrocytes in this study. RESULTS: To assess the route of Abeta uptake, we exposed cultured astrocytes to fluorescently labeled Abeta1-40 or Abeta1-42 together with chloropromazine (CP) or methyl-beta-cyclodextrin (MbetaCD), inhibitors of clathrin- and caveolin-dependent endocytosis, respectively. CP treatment almost completely blocked Abeta1-40 and Abeta1-42 endocytosis, whereas exposure to MbetaCD had no significant effect. Actin disruption with cytochalasin D (CytD) or latrunculin B also completely blocked Abeta1-40 and Abeta1-42 endocytosis. Because the absence of Mt3 also results in actin disruption, we examined Abeta1-40 and Abeta1-42 uptake and expression in Mt3 (-/-) astrocytes. Compared with wild-type (WT) cells, Mt3 (-/-) cells exhibited markedly reduced Abeta1-40 and Abeta1-42 endocytosis and expression of Abeta1-42 monomers and oligomers. A similar reduction was observed in CytD-treated WT cells. Finally, actin disruption and Mt3 knockout each increased the overall levels of clathrin and the associated protein phosphatidylinositol-binding clathrin assembly protein (PICALM) in astrocytes. CONCLUSIONS: Our results suggest that the absence of Mt3 reduces Abeta uptake in astrocytes through an abnormality in actin polymerization. In light of evidence that Mt3 is downregulated in AD, our findings indicate that this mechanism may contribute to the extracellular accumulation of Abeta in this disease. |
