# 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 previous sections on the in vitro and in vivo effects of monoterepenes provided a plethora of evidences linking these compounds with key pathological pathways of AD. The general mechanism of action of monoterepenes in the AD brain is depicted in Figure 4. Some of the key features of monoterepenes, particularly iridoids, as an emerging class of compounds as anti-AD agents are shown below. The role of A\(\beta\) in the pathology and as therapeutic target for AD has been reviewed in the various literatures (e.g., [88; 89; 90]). Recent review articles from our laboratories have also shown that many polyphenic compounds such the flavonoids, diterpenoids and cinamate derivatives display therapeutic potential for AD through multiple mechanisms involving A\(\beta\)[6; 7; 8; 9; 10; 11; 12; 13; 14]. Hence, the formation, aggregation and toxicity of A\(\beta\) can all serve as targets for therapeutic agents. The direct role of monoterepenes in the formation and aggregation of A\(\beta\) is however less clear and the observed activity at moderate concentration may not be of a high degree of therapeutic relevance. Never the less, direct effect on APP processing enzymes has been shown. The predominant forms of the pathological A\(\beta\) in the brain are A\(\beta\)1-40 and to a lesser extent A\(\beta\)1-42 which are formed through the amyloidgenic \(\beta\)-secretase-dependent pathway. The selective inhibition of this enzyme by monoterepenes (Table 1) without much effect on the non-amyloidogenic marker enzyme (\(\alpha\)-secretase) is an interesting finding. Figure 4: Therapeutic targets of iridoids and other monoterepenes discussed in this review. Antiinflammatory effect, amelioration of oxidative stress, mechanisms related to A\(\beta\) formation, aggregation and clearance, \(\tau\)-protein phosphorylation and aggregation, and neurotoxicity associated with mitochondrial dependent and independent mechanisms are among the therapeutic targets. A large body of evidence also suggests that monoterenes (Tables 1 and 2) ameliorate the A\(\beta\)-induced cytotoxicity both in cultured neuronal cells and various animal models of AD [6; 7; 8; 9; 10; 11; 12; 13; 14]. Upon aggregation, the A\(\beta\) oligomers induce neurotoxicity leading to cell death, impairment of synaptic function and behavioral deficits that are commonly observed in AD animal models. Hence, one major target of the iridoids as well as the selected other monoterenes appear to be mediated through mechanisms related to A\(\beta\) formation and/or toxicity. The role of ROS in A\(\beta\)-induced neurotoxicity has been well established from evidences mostly linking redox metals like copper, zinc, and iron coordinating the generation of toxic free radicals and/or ROS [91; 92; 93; 94; 95; 96; 97]. As inhibitors of ROS generation through direct metal chelation and ROS scavenging, the role of polyphenols as potential therapeutic agents for AD has been extensively studied. In this direction, our own studies on catechol functional group and the flavonoid skeleton as optimized structural moieties for biological effects have been exhaustively researched [98; 99; 100; 101; 102; 103; 104; 105]. The monoterenes presented in this communication however lack such structural moiety unless additional skeleton as that shown in oleuropein is added (Figure 3). Their effect on the amelioration of the A\(\beta\)-toxicity as well as neurotoxicity induced by H\({}_{2}\)O\({}_{2}\) suggest a mechanism of action beyond direct ROS scavenging. This can include boosting antioxidant defenses, and in this connection, numerous studies have shown an increased antioxidant status in the AD brain following treatment by monoterenes (Table 2). Another well-defined mechanism of action of monoterenes in the AD brain appears to be linked to anti-inflammatory effect.