Abstract
Neprilysin (NEP) is the most important Aβ-degrading enzyme. Its expression level decreases with age and inversely correlated with amyloid accumulation, suggesting its correlation with the late-onset of Alzheimer’s disease. Recently, many reports showed that upregulating NEP level is a promising strategy in the prevention and therapy of Alzheimer’s disease. Here, we used a sensitive fluorescence-based Aβ digestion assay to screen 25 curcumin analogs for their ability to upregulate NEP activity. To our surprise, four compounds, dihydroxylated curcumin, monohydroxylated demethoxycurcumin, and mono- and di-hydroxylated bisdemethoxycurcumin, increased NEP activity, while curcumin did not. The ability of these polyhydroxycurcuminoids to upregulate NEP was further confirmed by mRNA and protein expression levels in the cell and mouse models. Finally, feeding monohydroxylated demethoxycurcumin (also named demethylcurcumin) or dihydroxylated bisdemethoxycurcumin (also named bisdemethylcurcumin) to APPswe/PS1dE9 double transgenic mice upregulated NEP levels in the brain and reduced Aβ accumulation in the hippocampus and cortex. These polyhydroxycurcuminoids offer hope in the prevention of Alzheimer’s disease.
Highlights
Neprilysin (NEP) is the most important amyloid-β peptides (Aβ)-degrading enzyme
NEP has been singled out as the most promising target because (1) its protein levels are lower in Alzheimer’s disease (AD) brains than normal brains[4] and are inversely correlated with age[5]; (2) NEP mRNA levels are lower in high plaque density regions of human AD brains than in other regions or the corresponding regions of normal brains[6]; (3) NEP activity and protein levels in the hippocampus decline with age in mice[7]; (4) NEP protein levels are higher in the cerebellum of mice than in the cortex and hippocampus, regions of major Aβ plaque accumulation[7,8]; and (5) Aβ levels are twice as high in NEP knock out mice[3,9]
We measured the fluorescence increase caused by cleavage of a quenched fluorogenic peptide, qf-Aβ(1-7)C, which can be cleaved by NEP and insulin-degrading enzyme (IDE), but not by other Aβ-degrading enzymes (Fig. 2a)[28]
Summary
Neprilysin (NEP) is the most important Aβ-degrading enzyme. Its expression level decreases with age and inversely correlated with amyloid accumulation, suggesting its correlation with the late-onset of Alzheimer’s disease. Four compounds, dihydroxylated curcumin, monohydroxylated demethoxycurcumin, and mono- and di-hydroxylated bisdemethoxycurcumin, increased NEP activity, while curcumin did not The ability of these polyhydroxycurcuminoids to upregulate NEP was further confirmed by mRNA and protein expression levels in the cell and mouse models. Feeding monohydroxylated demethoxycurcumin ( named demethylcurcumin) or dihydroxylated bisdemethoxycurcumin ( named bisdemethylcurcumin) to APPswe/PS1dE9 double transgenic mice upregulated NEP levels in the brain and reduced Aβ accumulation in the hippocampus and cortex These polyhydroxycurcuminoids offer hope in the prevention of Alzheimer’s disease. Wang et al.[25] showed that feeding a high dose of curcumin (200 mg/kg/day) to an AD double transgenic mouse model (APPswe/PS1dE9) for 3 months reduced Aβ levels and increased NEP and IDE expression in the hippocampus and improved spatial learning and memory ability. We hypothesize that turmeric might have beneficial effect on maintaining the balance between anabolism and catabolism of Aβ by upregulating NEP and other curcumin analogs in turmeric might be more beneficial than curcumin
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