|Alzheimer > 17. Why Curcumin is NOT Effective for Alzheimer's Disease|
Curcumin is an active component of turmeric which has been commonly used as food additive and herbal medicine in Asia since ancient times. In 2001, two studies showed that curcumin could reduce oxidative damage and amyloid pathology in animal models of Alzheimer's disease (AD) (Lim et al., 2001; Frautschy et al., 2001). Since then, research interest in the biological effects of curcumin exploded. The number of published articles increases from ~ 100 in 2000 to over 1400 in 2013 (Figure 1).
In the last two decades, intensive research has revealed a few properties that curcumin may improve cognitive functions or reverse neurodegeneration, such as anti-amyloid, anti-oxidant, anti-inflammation and neurogenesis (Figure 2). In particular, curcumin has been shown to be a potent GSK-3β inhibitor (Bustanji et al., 2009), thus capable of attenuating Tau pathology (Chapter 6). Curcumin can also inhibit the aggregation of beta amyloid (Aβ) and Tau protein (Figure 3).
With these anti-neurodegeneration properties, one would expect curcumin to exert robust beneficial effects on neurodegenerative disorders, including AD. Surprisingly, most clinical trials did not show any improvement (Sarker and Franks, 2018; Kuszewski et al., 2018). There was even a trend for curcumin-treated subjects to do worse than placebo-treated subjects on the Mini-Mental State Examination (Zhu et al., 2019). The failure of curcumin in the treatment of AD is totally unexpected on the basis of Amyloid Cascade Hypothesis. However, it can be explained by the BDNF Cascade Hypothesis proposed in Chapter 12.
Curcumin has been demonstrated to reduce the level of miR-132 (Dolati et al., 2018a; Dolati et al., 2018b). miR-132 is irrelevant to AD in the Amyloid Cascade Hypothesis (Selkoe and Hardy, 2016), but according to BDNF Cascade Hypothesis, it plays a key role in tauopathy (including AD) by regulating the expression level of total and 4-repeat (4R) Tau protein. miR-132 reduction would increase total and 4R-Tau level (Chapter 10), thereby enhancing neuronal excitability (Chapter 9). In tauopathy, miR-132 is down-regulated (Chapter 11). Therefore, curcumin can exert detrimental effects on AD by reducing miR-132 level even further. The failure of curcumin shows that this single detrimental property is sufficient to negate all beneficial properties mentioned above, consistent with the critical role of miR-132 in AD.
Just the opposite of tauopathy, miR-132 is up-regulated in Parkinson's disease (PD) (Lungu et al., 2013). Therefore, curcumin could be used for the treatment of PD. I happen to have a friend with Parkinson's disease. Based on my understanding of PD, I recommended him to take curcumin on May 5, 2019. His symptoms have improved significantly. Details will be described in later chapters. The next chapter will discuss other preventive and therapeutic strategies for AD.
Author: Frank Lee