# Iridoids and Other Monoterpenes in the Alzheimer's Brain: Recent Development and Future Prospects
## 5 Insights into the Mechanism of Action of Iridoids and Other Monoterpenes in AD
The therapeutic approach of AD by upregulating IDE is however a tricky one, as IDE also selectively degrades insulin and its inhibitors are needed to improve glucose homeostasis (e.g., in diabetes). The role of iridoids in this regards is very interesting as geniposide has been shown to upregulate IDE [39] while displaying potent antidiabetic effect [17]. As IDE is degrading the monomeric form of A\(\beta\), it is preventing the formation of oligomers or aggregates that is prerequisite to A\(\beta\) cytotoxicity in neuronal cells. Hence, a clear line of evidence is now available for geniposide and/or other iridoids that showed a promise in the [PERSON]'s brain. The dual effect of iridoids in diabetes and AD is also manifested from the possible mechanism of action related to the \(\tau\) protein phosphorylation pathway. The formation of intracellular NFTs is a result of aggregation of the hyperphosphorylated \(\tau\)-protein. As a major component of the neuronal cytoskeleton, \(\tau\)-protein is closely associated with microtubules and aids a number of neuronal functions from axonal transport to neurite outgrowth [87; 149]. The function of \(\tau\) protein in stabilizing the microtubule to facilitate the normal neuronal function is governed by its phosphorylation which is regulated by a number of cellular kinases and phosphatases [150]. Consequently, \(\tau\) protein dysregulation is among the pathological hallmark of AD as in NFTs and hence serves as a target for drug therapy. Hyperphosphorylation of \(\tau\)-protein quickly initiates the formation of helical filaments and aggregates as seen in the NFTs of AD. This intern leads to microtubule disassembly and destabilization [151]. The signaling cascade in \(\tau\)-protein hyperphosphorylation has been shown to involve the GSK-3\(\beta\) that directly act on the protein (to phosphorylate it) and make it to disassociate with the microtubules [152; 153]. Hence, downregulating GSK-3\(\beta\) by drugs is essential in AD not only to regulate \(\tau\)-protein hyperphosphorylation but also to manage other deleterious effect of GSK-3\(\beta\) such as in ROS generation from the mitochondria. For example, GSK-3\(\beta\) has been shown to down-regulate the transcription factor Nrf2 after oxidative damage [154]. The GSK-3\(\beta\) itself is regulated by other kinases such as the Akt that phosphorylate GSK-3\(\beta\) at different sites to negatively regulate its activity. Furthermore, activation of PI3K triggers the activation of Akt that phosphorylates GSK-3\(\beta\) leading to inhibition of \(\tau\)-protein phosphorylation. Hence, the dysfunction of PI3K/Akt signaling is linked to \(\tau\)-protein phosphorylation or NFT formation in AD. The p38 MAPK is also emerged as anther kinase involved in \(\tau\)-protein phosphorylation and hence can be targeted by drugs [155; 156; 157]. A review article of such signal transduction pathways and possible pharmacological regulations is eloquently presented by [PERSON] et al. [158]. The observation of iridoids to regulate \(\tau\)-protein phosphorylation by inhibiting GSK-3\(\beta\) and regulation of the associated system primarily the PI3K/Akt signaling (Tables 1 and 2) is a remarkable documentation of record for this group of compounds. The pioneering compound in this regard is geniposide (e.g., [38; 39; 67]). Other natural products such phenolics including resveratrol [159], curcumin [160], hyperorin [161] and capsaicin [162] have been shown to display inhibitory effect against \(\tau\) protein hyperphosphorylation as well as affect in vivo models of AD. Hence, iridoids with structural feature distinctively different from polyphenols appear to share one common feature of mechanism in their potential AD modulations.