Fuzhisan ameliorates Aß production and tau phosphorylation in hippocampal of 11month old APP/PS1 transgenic mice: A Western blot study.

Accumulation of amyloid-ß (Aß) peptide and deposition of hyperphosphorylated tau protein are two major pathological hallmarks of Alzheimer's disease (AD). Glycogen synthase kinase-3ß (GSK3ß) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aß and through its well-established role on tau phosphorylation. The phosphoinositide 3 kinase (PI3K)/Akt pathway plays an import role in neuronal survival and cognitive function, and is known as an upstream element of GSK3ß. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment of AD for over 20years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. However, it still remains unclear whether FZS is responsible for regulation of PI3K/AKT/GSK3ß signaling and contributes to subsequent down-regulation of Aß and phosphorylated tau. Thus, we treated APP/PS1 transgenic mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 60days and Donepezil was used as a positive control. The results showed that treatment with FZS significantly reversed the memory deficit in the Tg APP/PS1 mice in the Morris water maze test. Moreover, FZS significantly attenuated Aß production through inhibition of APP procession and phosphorylation of tau in the hippocampus of Tg APP/PS1 mice. In addition, FZS treatment also increased PI3K and pSer473-AKT levels, inhibited GSK3ß activity by increasing phosphorylation of GSK3ß at Ser9. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the PI3K/AKT/GSK3ß signaling which may contribute to down-regulation of Aß and tau hyperphosphorylation.

Fuzhisan Ameliorates the Memory Deficits in Aged SAMP8 Mice via Decreasing Aß Production and Tau Hyperphosphorylation of the Hippocampus.

The pathological features of Alzheimer's disease (AD) include extracellular neuritic plaques containing ß-amyloid (Aß) peptide, a cleaved fragment of amyloid precursor protein (APP) via ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Cyclin-dependent kinase 5 (Cdk5) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aß and through its well-established role as a tau kinase. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment AD for over 20 years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. To investigate mechanisms of AD and the potential therapy of FZS in AD, we treated senescence-accelerated mouse SAMP8 mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 8 weeks and Donepizel was used as a positive control. The results showed that FZS (0.3, 0.6, and 1.2 g/kg/day) improved impaired cognitive ability of aged SAMP8 mice in a dose-dependent manner. FZS robustly decreased Aß level and phosphorylation of tau. This was accompanied by a significant decrease in the BACE1 level and phosphorylated APP (Thr668). Futhermore, The p25/Cdk5 pathway was markedly down-regulated by FZS treatment. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the p25/Cdk5 pathway which may contribute to down-regulation of Aß and tau hyperphosphorylation.