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Background  Astrocytes may play important roles in the pathogenesis of Alzheimer’s disease (AD) by clearing extracellular amyloid beta (Aβ) 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 Aβ, we investigated the possible role of Mt3 in Aβ endocytosis by cortical astrocytes in this study.    Results  To assess the route of Aβ uptake, we exposed cultured astrocytes to fluorescently labeled Aβ 1–40  or Aβ 1–42  together with chloropromazine (CP) or methyl-beta-cyclodextrin (MβCD), inhibitors of clathrin- and caveolin-dependent endocytosis, respectively. CP treatment almost completely blocked Aβ 1–40  and Aβ 1–42  endocytosis, whereas exposure to MβCD had no significant effect. Actin disruption with cytochalasin D (CytD) or latrunculin B also completely blocked Aβ 1–40  and Aβ 1–42  endocytosis. Because the absence of  Mt3  also results in actin disruption, we examined Aβ 1–40  and Aβ 1–42  uptake and expression in  Mt3   −/−   astrocytes. Compared with wild-type (WT) cells,  Mt3   −/−   cells exhibited markedly reduced Aβ 1–40  and Aβ 1–42  endocytosis and expression of Aβ 1-42  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 Aβ 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 Aβ in this disease.

Metallothionein-3 modulates the amyloid β endocytosis of astrocytes through its effects on actin polymerization