| Introduction: Alzheimer's disease (AD) is the most common form of dementia. It is characterized by the progressive loss of cognitive and intellectual functions and inevitably complete loss of the capability to take care of normal daily activities at the later stages of the disease. It is estimated that the prevalence will exceed 80 million worldwide by 2040, which will impose enormous economic pressure on any country. The cause of the disease remains incompletely elucidated. Based on histopathological and biochemical studies, it is manifested by neuroinflammation, with increasing levels of amyloid plaques and neurofibrillary tangles, loss of acetylcholine (Ach) and loss of neurons. Curcumin is a polyphenolic compound which possesses antioxidative and anti-inflammatory properties. Other studies demonstrated its abilities to reduce amyloid plaque burden and oxidative damage and to improve cognitive function of rodent models of AD. However, the physiological mechanisms by which curcumin achieved these functions are still poorly known, which hinders its development and use to treat AD.;Objective and methods: The main objective of this study was to determine the possible functions of curcumin in the hypothesized pathways of AD development. Cell free models of metal ion induced Abeta aggregation and hydrogen peroxide (H2O2) generation were used to determine the effectiveness of curcumin in reducing Abeta aggregates and H2O2, respectively, at physiologically attainable concentrations. An in vitro model was used to determine the effect of curcumin on the secretion of ApoE protein from the mouse microglial BV2 cell line. Transgenic mouse models, Tg2576, lNPL3 and lNPL3xTg2576, were used to determine the efficacies of curcumin on modulating the activities of (alpha-, beta- and gamma-secretases; on the expression of genes regulating Abeta metabolism, protecting against Abeta toxicity and regulating Ach homeostasis; and to determine if curcumin can be used to treat tauopathy.;Results: Our data showed that curcumin at concentrations achievable in vivo was effective at disrupting Abeta aggregates (IC50 < 0.9 muM), but it was ineffective at blocking H2O2 production (IC50 5.2 muM). In vitro study showed that curcumin was able to increase ApoE protein secretion from a mouse microglial cell line at physiologically attainable concentrations (0.064 to 1 muM, p<0.001). An animal study demonstrated that curcumin was incapable of modulating alpha-, beta- or gamma-secretase activity. Gene expression in animal models showed that curcumin was incapable of modulating genes regulating APP cleavage, but it was able to increase the expression of some substrates of secretases: Btc (+26%, p<0.005) and Kl (+96%, p<0.05). Among genes regulating Abeta degradation, curcumin was able to increase Ide (+23%, p<0.05), Mmp2 (+77%, p<0.05) and Mmp14 (+46%, p<0.005). Of genes acting as Abeta chaperones, curcumin was unable to cause any change. Among genes acting as Abeta receptors, curcumin was able to increase the expression of ApoeR2 (+37%, p<0.05), Lrp1 (+30%, p<0.05) and Msr1 (+46%, p<0.05). Of genes regulating Ach homeostasis, curcumin did not show any effect. Among genes providing protection against Abeta toxicity, curcumin was capable of increasing Igf2 (+130%, p<0.01) and Irs1 (+30%, p<0.01) and Irs1 (+30%, p<0.01). Of genes relating to antioxidative defences, curcumin was able to increase Nos2 (+25%, p<0.05), Sod3 (+60%, p<0.05) and Bmp6 (+46%, p<0.01) and suppress Nox1 (-43%, p<0.01). For treating tauopathy, curcumin was able to reduce NFT as measured by AT8-immunopositive area (-75%, p=0.02) in the medulla, but not in the entorhinal cortex or amygdala (p=0.89). The effect was only observed in 18 month old JNPL3 mice administered curcumin in peanut butter but not in 14 month old JNPL3 mice administered curcumin in chow. A rotarod study of 18 month old JNPL3 mice showed that curcumin was unable to improve motor function (p=0.67). Finally, on other phenotypic changes, curcumin was able to reduce both mortality (p=0.009) of all male mice and weight loss (p=0.007) of all mice.;Conclusion: Our data suggest that curcumm may reduce amyloid burden by increasing Abeta solubilization, degradation and efflux; it may provide protection against Abeta toxicity; and it may also increase antioxidative defences. For tauopathy, curcumin may reduce tangle formation, but more work is needed to confirm this function. Taken together, all the data in this study showed the physiologically relevant functions of curcumin, which favour its beneficial use for AD treatment. |
