Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder with complex pathogenesis. Emerging evidence indicates that there is a tight relationship between mitochondrial dysfunction and beta-amyloid (A beta) formation. 2,3,5,4'-Tetrahydroxystilbene-2-O-beta-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. The purpose of the present study was to investigate the effects of TSG on A beta production and neurotrophins in the brains of rats by using a mitochondrial dysfunction rat model induced by sodium azide (NaN3), an inhibitor of mitochondrial cytochrome c oxidase (COX). NaN3 was administered to rats by continuous subcutaneous infusion for 28 days via implanted osmotic minipumps to establish the animal model. TSG was intragastrically administered starting 24 h after the operation. The activity of mitochondrial COX was measured by a biochemical method. The content of A beta 1-42 was detected by ELISA. The expression of neurotrophic factors was determined by Western blot and immunohistochemistry. The results showed that NaN3 infusion for 28 days induced a decrease in mitochondrial COX activity, an increase in A beta 1-42 content and the expression of amyloidogenic beta-amyloid precursor protein (APP), beta-site APP cleaving enzyme 1 (BACE1) and presenilin 1 (PS1), and a decline in the expression of neurotrophins in the hippocampus of rats. Intragastrical administration of TSG elevated mitochondrial COX activity, decreased A beta 1-42 content and the expression of APP, BACE1 and PS1, and enhanced the expression of nerve growth factor, brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) in the hippocampus of NaN3-infused rats. These findings suggest that TSG may be beneficial in blocking or slowing the progression of AD by enhancing mitochondrial function, decreasing A beta production and increasing neurotrophic factors at some extent.