# Iridoids and Other Monoterpenes in the Alzheimer's Brain: Recent Development and Future Prospects
## 4 Therapeutic Potential for Alzheimer's Disease
### Evidence of Efficacy Demonstrated through In Vivo Studies
Moreover, catalpol in this model has been shown to reverse the suppressed level of muscarinic acetylcholine (ACh) receptor M1 while concomitantly suppressing the level of inflammatory and oxidant markers (TNF-\(\alpha\), IL-1 and advanced glycation end products (AGEs)) [60]. Improvement of memory deficit along with antioxidant markers (glutathione S-transferase (GSH-ST), glutamine synthetase (GS) and creatine kinase (CK) have also been shown for catalpol [61; 63]. In other experiments, A\(\beta\) was directly injected into the brain to study the biochemical and behavioral changes in animals. Catalpol was among the iridoids showing activity in this model where prevention of the ACh neuronal damage was noted from the increased level of choline CHAT positive cells density in cerebral cortex as well as increased level of ChAT activity [28]. Geniposide also ameliorated the A\(\beta\)-induced neuronal abnormalities including cellular densities and synaptic proteins level in the transgenic mice model [63]. On the other hand, linalool has been shown to reverse cognitive deficits and altered the level of the antioxidant and protein (SOD, GPx, AChE) levels/activity in mice injected with A\(\beta\)[69]. The effect of paeoniflorin in memory improvement and protection of animals from A\(\beta\) through mechanisms including enhancing antioxidant defenses (e.g., GSH) and calcium homeostasis have also been reported [76; 77]. [PERSON] et al. [62] employed the APP/PS1 Transgenic mouse model of AD to study the potential benefit of geniposide. The insulin deficiency induced by streptozotocin (STZ) in these wild-type transgenic animals appeared to enhance the GSK-3\(\beta\) level/activity which was suppressed by geniposide administration in a dose dependent manor. It is worth noting that the doses employed here were very small (5, 10, and 20 mg/kg). The data were also in line with the broader effect of geniposide in signal transduction pathways related to insulin resistance reviewed recently [17]. The GSK-3\(\beta\) plays direct role in \(\tau\) protein hyperphosphorylation [86; 87]. The role of the Akt in the regulation of GSK-3\(\beta\) is also well understood and its phosphorylation initiates its inactivation that appeared to be modulated by geniposide. In agreement with this data, geniposide can also regulate the phosphorylation of \(\tau\) protein both in the insulin-dependent and independent manor in primary cultured cortical neurons [63]. It does also enhance the phosphorylation of Akt at Ser473 and Thr308 sites [63]. The dual effect of geniposide both in diabetes and AD is thus evident from its effect on the phosphorylation of \(\tau\) protein via the PI3K-GSK-3\(\beta\) kinase pathway. To date, hyperphosphorylated \(\tau\) protein is one of the pathological hallmark of AD as it is the principal component of neurofibrillary tangles (NFTs) [87]. The structural integrity of \(\tau\) protein is regulated by a cascade of phosphorylation-related pathways, and hence both kinases and phosphatases play important roles in stable NFT formation. The GSK-3\(\beta\) being the key player in the kinase--mediated hyperphosphorylation of \(\tau\) protein, its regulation by geniposide seems to shed some light into the possible mechanism of iridoids' action. The crosstalk between diabetes and AD was also highlighted by [PERSON] et al. [67] who confirmed the potential role of geniposide through GSK-3\(\beta\) regulation. Similarly, in the study by [PERSON] et al. [68], geniposide has been shown to decrease the A\(\beta\)1-42 level while improving the expression of IDE in A\(\beta\)-treated STZ-induced diabetic rats. In the further experiment on transgenic mice model, geniposide was shown to improve learning and memory along with antiinflammatory effect (through suppression of RAGE-dependent signaling in activation of ERK and IkB/NF-\(\kappa\)B and the production of TNF-\(\alpha\), IL-1\(\beta\)) and lowering the A\(\beta\) level in the cerebrum [65].