P3-431: Effects of tetrahydroxystilbene glucoside on multiple targets of Alzheimer's disease in seven Alzheimer-like animal models

Tetrahydroxystilbene glucoside (TSG) is a main effective component extracted from Polygonum multiflorum which is a traditional Chinese herb for anti-aging. In our previous studies TSG showed neuroprotective effect in cell model induced by Aβ, and inhibited β-secretase activity in vitro. The purpose of the present study was to investigate whether TSG was effective to treat AD in vivo. TSG was intragastrically administered to 7 kinds of AD-like animal models. The learning and memory abilities were measured by Morris water maze and step-through tests. Morphological changes were observed under electro-microscopy. The expression of specific proteins was detected by immunohistochemistry and Western blot analysis. The enzymic activity and cytokines were measured by biochemical assays. (1) In APP transgenic mice, TSG decreased amyloid plaques, Aβ and presenelin-1 in hippocampus. (2) In Aβ1-40 brain ventricle injection mouse model, TSG decreased IL-1 and malondialdehyde (MDA), and protected ultrastructure of mitochondria and neurons in hippocampus. (3) In cholinergic damage rats induced by forebrain injection of IBO, TSG increased the ChAT activity and M-cholinergic receptor in hippocampus and cerebral cortex. (4) In aged rats, TSG decreased loss of cholinergic neurons and synapses, protected synaptic ultrastructure, enhanced expression of synaptophysin, NGF and TrkA, and promoted signal transduction for neuron survival including IRS-1, p-CREB and p70S6K in hippocampus. (5) In brain aging mouse model induced by D-galactose injection, TSG decreased MDA, increased glutathion and SOD, and enhanced NGF and TrkA in hippocampus and cerebral cortex. (6) In dementia rat model induced by hypercholesterolemia, TSG decreased Aβ in hippocampus, and declined cholesterol and LDL in serum. (7) In dementia rat model induced by chronic cerebral ischemia, TSG decreased neuron death and MDA content, increased glutathion peroxidase activity and expression of PP2A and MAP-2 in hippocampus. (8) TSG improved learning-memory impairment in all above model animals. TSG improves learning-memory ability in 7 kinds of AD-like animal models. Its mechanisms are involved in antagonizing multiple targets in AD pathogenesis. TSG may have strong potentials for treating AD. This natural product has finished Phase I clinical trial and started Phase II clinical trial to treat AD in China.