Resveratrol Abrogates Hypoxia-Induced Up-Regulation of Exosomal Amyloid-β Partially by Inhibiting CD147.

Hypoxia promotes both total extracellular and exosomal amyloid-β (Aβ) production and aggravates Alzheimer's disease (AD). Resveratrol (RSV) has been proved to be neuroprotective in AD models, and down-regulated the expression of CD147, an additional subunit of γ-secretase. In this study, we aimed to explore the role and mechanisms of RSV in hypoxia-induced upregulation of Aβ, especially exosomal Aβ. SH-SY5Y cells and HEK293 cells overexpressing amyloid precursor protein (APP) as well as C57BL/6 mice were treated with RSV and exposed to hypoxic conditions. The expression of SIRT1 or CD147 was modulated by transfection of specific siRNAs or plasmid. Aβ1-40 and Aβ1-42 levels were determined by ELISA. Hypoxia increased the levels of both Aβ1-40 and Aβ1-42 in the hippocampal lysates and serum-derived exosomes of mice. Hypoxia also increased both Aβ1-40 and Aβ1-42 levels in the total culture medium (CM), cell-derived exosomal lysates, and exosome-free CM of both cell lines. Treatment with RSV abrogated these changes in Aβ expression, inhibited the hypoxia-induced down-regulation of SIRT1 and up-regulation of CD147. Knockdown of SIRT1 promote total Aβ level but has no effect on exosomal Aβs expression. Knockdown of CD147 inhibits both total and exosomal Aβs expression. Furthermore, overexpressing CD147 in cells exposed to hypoxia facilitated the production of Aβ1-40 and Aβ1-42, while application of RSV reduced the CD147 expression as well as Aβ levels in both exosomes and exosome-free CM. These results suggested that RSV abrogated hypoxia-induced up-regulation of total and exosomal Aβ partially by inhibiting CD147.