Curcumin analogue C66 ameliorates the pathology of Alzheimer's disease through suppression of JNK signaling pathway.

Oxidative stress and neuroinflammation are two key pathological features in the early stage of Alzheimer's disease (AD), and they promote each other to further drive the progression of AD. Therefore, the development of therapeutic agents with dual anti-inflammatory and antioxidant properties represents a promising strategy for AD treatment. C66, a synthetic derivative of curcumin, protected PC12 cells and primary neurons from oxidative damage caused by Aβ. In addition, C66 alleviated Aβ-induced excessive inflammatory response in BV2 cells. Further results showed that C66 reduced neuroinflammation and neuronal apoptosis, ultimately improved cognitive decline in APPswe/PSEN1dE9 (APP/PS1) double transgenic AD mice. Importantly, C66 exhibited superior improved properties in APP/PS1 mice compared with the clinical control drug donepezil. Mechanistically, we indicated that C66 conferred its neuroprotective effects by inhibiting c-Jun N-terminal kinase (JNK) pathway. The result was further confirmed by using SP600125, a specific JNK inhibitor. Together, our findings suggest that C66 is expected to be further developed as a drug candidate for AD therapy.