The Ongoing Search for Small Molecules to Study Metal-Associated Amyloid-β Species in Alzheimer's Disease

CONSPECTUS: The development of a cure for Alzheimer's disease (AD) has been impeded by an inability to pinpoint the root cause of this disorder. Although numerous potential pathological factors have been indicated, acting either individually or mutually, the molecular mechanisms leading to disease onset and progression have not been clear. Amyloid-beta (A beta), generated from proteolytic processing of the amyloid precursor protein (APP), and its aggregated forms, particularly oligomers, are suggested as key pathological features in AD-affected brains. Historically, highly concentrated metals are found colocalized within A beta plaques. Metal binding to A beta (metal-A beta) generates/stabilizes potentially toxic A beta oligomers, and produces reactive oxygen species (ROS) in vitro (redox active metal ions; plausible contribution to oxidative stress). Consequently, clarification of the relationship between A beta, metal ions, and toxicity, including oxidative stress via metal-A beta, can lead to a deeper understanding of AD development. To probe the involvement of metal-A beta in AD pathogenesis, rationally designed and naturally occurring molecules have been examined as chemical tools to target metal-A beta species, modulate the interaction between the metal and A beta, and subsequently redirect their aggregation into nontoxic, off-pathway unstructured aggregates. These ligands are also capable of attenuating the generation of redox active metal-A beta-induced ROS to mitigate oxidative stress. One rational design concept, the incorporation approach, installs a metal binding site into a framework known to interact with A beta. This approach affords compounds with the simultaneous ability to chelate metal ions and interact with A beta. Natural products capable of A beta interaction have been investigated for their influence on metal-induced A beta aggregation and have inspired the construction of synthetic analogues. Systematic studies of these synthetic or natural molecules could uncover relationships between chemical structures, metal/A beta/metal-A beta interactions, and inhibition of A beta/metal-A beta reactivity (i.e., aggregation modes of A beta/metal-A beta; associated ROS production), suggesting mechanisms to refine the design strategy. Interdisciplinary investigations have demonstrated that the designed molecules and natural products control the aggregation pathways of metal-A beta species transforming their size/conformation distribution. The aptitude of these molecules to impact metal-A beta aggregation pathways, either via inhibition of A beta aggregate formation, most importantly of oligomers, or disaggregation of preformed fibrils, could originate from their formation of complexes with metal-A beta. Potentially, these molecules could direct metal-A beta size/conformational states into alternative nontoxic unstructured oligomers, and control the geometry at the A beta-ligated metal center for limited ROS formation to lessen the overall toxicity induced by metal-A beta. Complexation between small molecules and A beta/metal-A beta has been observed by nuclear magnetic resonance spectroscopy (NMR) and ion mobility-mass spectrometry (IM-MS) pointing to molecular level interactions, validating the design strategy. In addition, these molecules exhibit other attractive properties, such as antioxidant capacity, prevention of ROS production, potential blood-brain barrier (BBB) permeability, and reduction of A beta-/metal-A beta-induced cytotoxicity, making them desirable tools for unraveling AD complexity. In this Account, we summarize the recent development of small molecules, via both rational design and the selection and modification of natural products, as tools for investigating metal-A beta complexes, to advance our understanding of their relation to AD pathology.