Purpose: To investigate the mRNA and protein alterations of alpha-synuclein in the brain of Alzheimer's disease-like mouse model at the different ages, and to evaluate the effects of 2,3,5,4'-tetrahydroxy stilbene-2-O-beta-D-glucoside (TSG) on alpha-synuclein expression. Methods: TSG (120 or 240 mu mol kg(-1)d(-1)) was intragastrically administered to APPV717I transgenic (Tg) mice at 4- or 10-month-old for 6 months. Results: mRNA expression of alpha-synuclein increased in hippocampus in 4 month to 16 month old Tg mice compared with age-matched control. alpha-synuclein protein expression in hippocampus also increased in 4 month to 16 month old Tg mice significantly. Significant down-regulation of alpha-synuclein mRNA and protein expression in hippocampus was found after treatment of TSG for 6 months in both 10- and 16-month-old Tg mice. Production of dimer and tetramer of alpha-synuclein protein in Tg mice was inhibited after treatment with TSG. Conclusions: The expression and aggregation of alpha-synuclein was age-dependently increased in Tg mice. TSG not only prevents over-expression of alpha-synuclein at an early stage, but also reverses the increased expression of alpha-synuclein and inhibits the aggregation at the late stage of Tg mice. TSG may have potential to the prevention and treatment of Alzheimer's diseases.