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

Abstract

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-β (Aβ), 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 Aβ plaques. Metal binding to Aβ (metal-Aβ) generates/stabilizes potentially toxic Aβ oligomers, and produces reactive oxygen species (ROS) in vitro (redox active metal ions; plausible contribution to oxidative stress). Consequently, clarification of the relationship between Aβ, metal ions, and toxicity, including oxidative stress via metal-Aβ, can lead to a deeper understanding of AD development. To probe the involvement of metal-Aβ in AD pathogenesis, rationally designed and naturally occurring molecules have been examined as chemical tools to target metal-Aβ species, modulate the interaction between the metal and Aβ, and subsequently redirect their aggregation into nontoxic, off-pathway unstructured aggregates. These ligands are also capable of attenuating the generation of redox active metal-Aβ-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 Aβ. This approach affords compounds with the simultaneous ability to chelate metal ions and interact with Aβ. Natural products capable of Aβ interaction have been investigated for their influence on metal-induced Aβ aggregation and have inspired the construction of synthetic analogues. Systematic studies of these synthetic or natural molecules could uncover relationships between chemical structures, metal/Aβ/metal-Aβ interactions, and inhibition of Aβ/metal-Aβ reactivity (i.e., aggregation modes of Aβ/metal-Aβ; 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-Aβ species transforming their size/conformation distribution. The aptitude of these molecules to impact metal-Aβ aggregation pathways, either via inhibition of Aβ aggregate formation, most importantly of oligomers, or disaggregation of preformed fibrils, could originate from their formation of complexes with metal-Aβ. Potentially, these molecules could direct metal-Aβ size/conformational states into alternative nontoxic unstructured oligomers, and control the geometry at the Aβ-ligated metal center for limited ROS formation to lessen the overall toxicity induced by metal-Aβ. Complexation between small molecules and Aβ/metal-Aβ has been observed by nuclear magnetic resonance spectroscopy (NMR) and ion mobility-mass spectrometry (IM...

Structure-based development of nitroxoline derivatives as potential multifunctional anti-Alzheimer agents

“…34 Encouraging in vitro results affecting several abnormalities observed in AD afflicted brain (i.e., metal miscompartmentalization, oxidative stress, Aβ aggregation) and clinical safety profiles of these compounds provide strong basis for incorporation of these substructures in new multifunctional compounds. 29,31,34,35 The 2,3-dihydro-1H-indene of 1 was in some molecules exchanged with the benzoxazole and benzothiazole moieties, which are, similarly as indene derivatives, known for their binding to Aβ aggregates. Low-molecular-weight molecules that incorporate these fragments have been used for Aβ plaque imaging and aggregation studies (e.g., the thioflavin T assay).…”

“…24,[26][27][28] Importantly, complexes of Aβ with redox-active metals, such as Cu and Fe, can generate reactive oxygen species (ROS), and therefore can trigger physiological responses to oxidative stress and peroxidation of lipids. 22,26 Aβ aggregation pathways and kinetics might themselves be affected by metal binding, which would result in potentially more toxic protease-resistant aggregates and oligomers [29][30][31] While Cu remains an interesting target in AD treatment, due to its important role in AD pathogenesis and its central role in redox cycling, care needs to be taken not to modify the homeostasis of other crucial divalent ions (e.g., Ca 2+ , Mg 2+ ) when targeting Cu. 31,32 Therefore, the design of multifunctional compounds that can chelate specific metal ions, reduce Aβ aggregation, and inhibit BChE are of major therapeutic interest.…”

“…22,26 Aβ aggregation pathways and kinetics might themselves be affected by metal binding, which would result in potentially more toxic protease-resistant aggregates and oligomers [29][30][31] While Cu remains an interesting target in AD treatment, due to its important role in AD pathogenesis and its central role in redox cycling, care needs to be taken not to modify the homeostasis of other crucial divalent ions (e.g., Ca 2+ , Mg 2+ ) when targeting Cu. 31,32 Therefore, the design of multifunctional compounds that can chelate specific metal ions, reduce Aβ aggregation, and inhibit BChE are of major therapeutic interest. 33 Indeed, 8-hydroxyquinoline-based compounds, including clioquinol, and its derivative PBT2, have reached phase II clinical studies as anti-AD therapies.…”

“…25,[29][30][31][32][33]36,37 Additionally, compounds with 8-hydroxyquinoline core displayed promising results in some other therapeutic areas (i.e., potential inhibitors of retroviral integrases, inhibitors of cathepsin B). 38,39 Modulation of the cholinergic and glutamatergic systems has also been aimed at slowing AD progression and controlling AD symptoms; however, there are no internationally approved therapeutics that can counteract the neurodegeneration associated with AD with sufficient efficacy and with a good safety profile.…”

Application of quinazoline and pyrido[3,2-d]pyrimidine templates to design multi-targeting agents in Alzheimer's disease

“…19,20 Due to the role of iron in promoting oxidative stress in AD [21][22][23] and its contribution in the formation of neurotoxic Ab plaques and neurobrillary tangles (NFTs), we assessed the Fe 2+ -chelation potential of the pyrido [3,2-d]pyrimidines (Table 3) in ferrozine based assay. The known iron chelators clioquinol and deferroxamine were used as reference agents.…”