Geniposide Ameliorates Learning Memory Deficits, Reduces Tau Phosphorylation and Decreases Apoptosis via GSK3β Pathway in Streptozotocin‐Induced Alzheimer Rat Model

Abstract

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.

Neuroprotective effects of geniposide on Alzheimer’s disease pathology

“…Current strategies include decreasing τ aggregation, blocking abnormal τ phosphorylation, or stopping the spread of τ pathology through the brain. Our previous study (Gao et al, 2014) showed that geniposide could greatly reverse τ hyperphosphorylation and the paired helical filament-like structures induced by STZ. Furthermore, we also showed that the neuroprotective effect of geniposide was blocked by wortmannin, a PI3K inhibitor.…”

“…Increasing studies have focused on the neuroprotective effect of geniposide in brain diseases, especially neurodegenerative disorders. Its protective effect from memory impairment and the normalization of objection recognition has been shown in animal behavioral experiments (Gao et al, 2014;Lv et al, 2014). Using a high-throughput screen for GLP-1R agonists, geniposide was identified as an agonist for GLP-1R (Liu et al, 2006).…”

“…This pathway involves the stimulation of PI3K binding to IRS and G protein, and the activation of PI3K and protein kinase B/Akt, which suppresses the induction of apoptosis and thereby protects neurons . (3) The activation of GSK3 modifies the cellular skeleton and dynamics by mediating the phosphorylation levels of τ protein, modulating the cleavage of APP, and improving learning and memory formation ( Eldar-Finkelman et al, 1999;Gao et al, 2011Gao et al, , 2014. As well, AMPK inhibits the mammalian target of rapamycin complex resulting in autophagy stimulation.…”

Potentials of incretin‐based therapies in dementia and stroke in type 2 diabetes mellitus

“…ICV‐infused (Val 8 )GLP‐1 and geniposide (a GLP‐agonist) prevented against Aβ‐induced decline of spatial learning70, 71. Peripherally‐administered exenatide and liraglutide prevented or improved memory performance in various rodent models of AD72, 73, 74, including in one late stage AD model75, and one diabetes‐related AD model76.…”

Leptin signaling plays a critical role in the geniposide-induced decrease of tau phosphorylation

“…Geniposide could also attenuate the level of Aβ and tau phosphorylation in streptozotocin (STZ)-induced diabetic rats [10,11]. But the role of leptin signaling on geniposide-regulating tau phosphorylation remains to be explored.…”