Effects and mechanism of amyloid β1-42 on mitochondria in astrocytes.

Abstract

Amyloid β (Aβ)1–42 is strongly associated with Alzheimer's disease (AD). The effects of Aβ1–42 on astrocytes remain largely unknown. The present study focused on the effects of Aβ1–42 on U87 human glioblastoma cells as astrocytes for in vitro investigation and mouse brains for in vivo investigation. The mechanism and regulation of mitochondria and cytochrome P450 reductase (CPR) were also investigated. As determined by MTT assays, low doses of Aβ1–42 (<1 µM) marginally promoted astrocytosis compared with the 0 µM group within 24 h, however, after 48 h treatment these doses reduced cellular growth compared with the 0 µM group. Furthermore, Aβ1–42 doses >5 µM inhibited the growth of U87 cells compared with the 0 µM group after 24 and 48 h treatment. Immunofluorescence analysis demonstrated that astrocytosis was also observed in early stage AD mice compared with wild-type (WT) mice. In addition, concentrations of Aβ1–42 were also significantly higher in early stage AD mice compared with WT mice, however, the levels were markedly lower compared with later stage AD mice, as determined by ELISA. In addition to increased levels of Aβ1–42 in mice with later stage AD, reduced astrocyte staining was observed compared with WT mice. Western blotting indicated that the effect of Aβ1–42 on U87 cell apoptosis may be regulated via Bcl-2 and caspase-3 located in mitochondria, whose functions, including adenosine triphosphate generation, electron transport chain and mitochondrial membrane potential, were inhibited by Aβ1–42. During this process, the expression and activity of cytochrome P450 reductase was also downregulated. The current study provides novel insight into the effects of Aβ1–42 on astrocytes and highlights a potential role for astrocytes in the protection against AD.