Geniposide Ameliorates Learning Memory Deficits, Reduces Tau Phosphorylation and Decreases Apoptosis via GSK 3β Pathway in Streptozotocin‐Induced A lzheimer Rat Model

Intracerebral‐ventricular ( ICV ) injection of streptozotocin ( STZ ) induces an insulin‐resistant brain state that may underlie the neural pathogenesis of sporadic A lzheimer disease ( AD ). Our previous work showed that prior ICV treatment of glucagon‐like peptide‐1 ( GLP ‐1) could prevent STZ ‐induced learning memory impairment and tau hyperphosphorylation in the rat brain. The C hinese herbal medicine geniposide is known to relieve symptoms of type 2 diabetes. Because geniposide is thought to act as a GLP ‐1 receptor agonist, we investigated the potential therapeutic effect of geniposide on STZ ‐induced AD model in rats. Our result showed that a single injection of geniposide (50 μM, 10 μL) to the lateral ventricle prevented STZ ‐induced spatial learning deficit by about 40% and reduced tau phosphorylation by about 30% with M orris water maze test and quantitative immunohistochemical analysis, respectively. It has been known that tau protein can be phosphorylated by glycogen synthase kinase‐3 ( GSK 3) and STZ can increase the activity of GSK 3β. Our result with W estern blot analysis showed that central administration of geniposide resulted in an elevated expression of GSK3β( pS ‐9) but suppressed GSK 3β( pY ‐216) indicating that geniposide reduced STZ ‐induced GSK 3β hyperactivity. In addition, ultrastructure analysis showed that geniposide averted STZ ‐induced neural pathology, including paired helical filament ( PHF )‐like structures, accumulation of vesicles in synaptic terminal, abnormalities of endoplasmic reticulum ( ER ) and early stage of apoptosis. In summary, our study suggests that the water soluble and orally active monomer of C hinese herbal medicine geniposide may serve as a novel therapeutic agent for the treatment of sporadic AD .