ABSTRACT
The insulin-degrading enzyme (IDE) possesses a strong ability to degrade insulin and Aß42 that has been linked to the neurodegeneration in Alzheimer's disease (AD). Given this, an attractive IDE-centric strategy for the development of therapeutics for AD is to boost IDE's activity for the clearance of Aß42 without offsetting insulin proteostasis. Recently, we showed that resveratrol enhances IDE's activity toward Aß42. In this work, we used a combination of chromatographic and spectroscopic techniques to investigate the effects of resveratrol on IDE's activity toward insulin. For comparison, we also studied epigallocatechin-3-gallate (EGCG). Our results show that the two polyphenols affect the IDE-dependent degradation of insulin in different ways: EGCG inhibits IDE while resveratrol has no effect. These findings suggest that polyphenols provide a path for developing therapeutic strategies that can selectively target IDE substrate specificity.
ABSTRACT
The amyloid-ß (Aß) peptide and tau protein are thought to play key neuropathogenic roles in Alzheimer's disease (AD). Both Aß and tau self-assemble to form the two major pathological hallmarks of AD: amyloid plaques and neurofibrillary tangles, respectively. In this review, we show that naturally occurring polyphenols abundant in fruits, vegetables, red wine, and tea possess the ability to target pathways associated with the formation of assemblies of Aß and tau. Polyphenols modulate the enzymatic processing of the amyloid-ß precursor protein and inhibit toxic Aß oligomerization by enhancing the clearance of Aß42 monomer, modulating monomer-monomer interactions and remodeling oligomers to non-toxic forms. Additionally, polyphenols modulate tau hyperphosphorylation and inhibit tau ß-sheet formation. The anti-Aß-self-assembly and anti-tau-self-assembly effects of polyphenols increase their potential as preventive or therapeutic agents against AD, a complex disease that involves many pathological mechanisms.
