Intracerebral-ventricular (ICV) injection of
streptozotocin (STZ) induces an
insulin-resistant brain state that may underlie the neural pathogenesis of sporadic
Alzheimer 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 Chinese 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 Morris water maze test and quantitative immunohistochemical analysis, respectively. It has been known that
tau protein can be phosphorylated by
glycogen synthase kinase-3 (GSK3) and STZ can increase the activity of GSK3β. Our result with Western blot analysis showed that central administration of
geniposide resulted in an elevated expression of GSK3β(pS-9) but suppressed GSK3β(pY-216) indicating that
geniposide reduced STZ-induced GSK3β 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 Chinese herbal medicine
geniposide may serve as a novel therapeutic agent for the treatment of sporadic AD.