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-β protein (Aβ), a ∼4 kDa peptide generated through serial cleavage of the amyloid-β protein precursor (AβPP) by β- and γ-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 Aβ deposition in an AD transgenic mouse model. Here, we elucidated the mechanisms of this analog on Aβ levels and AβPP 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 Aβ levels in conditioned media and reduces oligomeric amyloid levels in the cells. Furthermore, like curcumin, the lead compound attenuates the maturation of AβPP in the secretory pathway. Interestingly, it upregulated α-secretase processing of AβPP and inhibited β-secretase processing of AβPP by decreasing BACE1 protein levels. Collectively, our data reveal mechanisms of a promising curcumin analog in reducing Aβ levels, which strongly support its development as a potential therapeutic for AD.