A Curcumin Analog Reduces Levels of the Alzheimer's Disease-Associated Amyloid-β Protein by Modulating AβPP Processing and Autophagy

Alzheimer's disease (AD) is a devastating neurodegenerative disease with no cure currently available. A pathological hallmark of AD is accumulation and deposition of amyloid-beta protein (A beta), a similar to 4 kDa peptide generated through serial cleavage of the amyloid-beta protein precursor (A beta PP) by beta- and gamma-secretases. Curcumin is a natural compound primarily found in the widely used culinary spice, turmeric, which displays therapeutic potential for AD. Recently, we reported the development of curcumin analogs and identified a lead compound, curcumin-like compound-R17 (CLC-R17), that significantly attenuates A beta deposition in an AD transgenic mouse model. Here, we elucidated the mechanisms of this analog on A beta levels and A beta PP processing using cell models of AD. Using biochemical methods and our recently developed nanoplasmonic fiber tip probe technology, we showed that the lead compound potently lowers A beta levels in conditioned media and reduces oligomeric amyloid levels in the cells. Furthermore, like curcumin, the lead compound attenuates the maturation of A beta PP in the secretory pathway. Interestingly, it upregulated beta-secretase processing of A beta PP and inhibited beta-secretase processing of A beta PP by decreasing BACE1 protein levels. Collectively, our data reveal mechanisms of a promising curcumin analog in reducing A beta levels, which strongly support its development as a potential therapeutic for AD.