Reactivity of Metal-Free and Metal-Associated Amyloid-ß with Glycosylated Polyphenols and Their Esterified Derivatives.

Both amyloid-ß (Aß) and transition metal ions are shown to be involved in the pathogenesis of Alzheimer's disease (AD), though the importance of their interactions remains unclear. Multifunctional molecules, which can target metal-free and metal-bound Aß and modulate their reactivity (e.g., Aß aggregation), have been developed as chemical tools to investigate their function in AD pathology; however, these compounds generally lack specificity or have undesirable chemical and biological properties, reducing their functionality. We have evaluated whether multiple polyphenolic glycosides and their esterified derivatives can serve as specific, multifunctional probes to better understand AD. The ability of these compounds to interact with metal ions and metal-free/-associated Aß, and further control both metal-free and metal-induced Aß aggregation was investigated through gel electrophoresis with Western blotting, transmission electron microscopy, UV-Vis spectroscopy, fluorescence spectroscopy, and NMR spectroscopy. We also examined the cytotoxicity of the compounds and their ability to mitigate the toxicity induced by both metal-free and metal-bound Aß. Of the polyphenols investigated, the natural product (Verbascoside) and its esterified derivative (VPP) regulate the aggregation and cytotoxicity of metal-free and/or metal-associated Aß to different extents. Our studies indicate Verbascoside represents a promising structure for further multifunctional tool development against both metal-free Aß and metal-Aß.

A rationally designed small molecule for identifying an in vivo link between metal-amyloid-ß complexes and the pathogenesis of Alzheimer's disease.

Multiple factors, including amyloid-ß (Aß), metals, and reactive oxygen species (ROS), are involved in the development of Alzheimer's disease (AD). Metal ions can interact with Aß species generating toxic oligomers and ROS in vitro; however, the involvement of metal-Aß complexes in AD pathology in vivo remains unclear. To solve this uncertainty, we have developed a chemical tool (L2-b) that specifically targets metal-Aß complexes and modulates their reactivity (i.e., metal-Aß aggregation, toxic oligomer formation, and ROS production). Through the studies presented herein, we demonstrate that L2-b is able to specifically interact with metal-Aß complexes over metal-free Aß analogues, redirect metal-Aß aggregation into off-pathway, nontoxic less structured Aß aggregates, and diminish metal-Aß-induced ROS production, overall mitigating metal-Aß-triggered toxicity, confirmed by multidisciplinary approaches. L2-b is also verified to enter the brain in vivo with relative metabolic stability. Most importantly, upon treatment of 5XFAD AD mice with L2-b, (i) metal-Aß complexes are targeted and modulated in the brain; (ii) amyloid pathology is reduced; and (iii) cognition deficits are significantly improved. To the best of our knowledge, by employing an in vivo chemical tool specifically prepared for investigating metal-Aß complexes, we report for the first time experimental evidence that metal-Aß complexes are related directly to AD pathogenesis.