The Ongoing Search for Small Molecules to Study Metal-Associated Amyloid-尾 Species in Alzheimer鈥檚 Disease
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- 作者：Masha G. Savelieff ; Alaina S. DeToma ; Jeffrey S. Derrick ; Mi Hee Lim
- 刊名：Accounts of Chemical Research
- 出版年：2014
- 出版时间：August 19, 2014
- 年：2014
- 卷：47
- 期：8
- 页码：2475-2482
- 全文大小：332K
- ISSN：1520-4898
文摘
Conspectus
The development of a cure for Alzheimer鈥檚 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-尾 (A尾), 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尾 plaques. Metal binding to A尾 (metal鈥揂尾) generates/stabilizes potentially toxic A尾 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尾, metal ions, and toxicity, including oxidative stress via metal鈥揂尾, can lead to a deeper understanding of AD development.
To probe the involvement of metal鈥揂尾 in AD pathogenesis, rationally designed and naturally occurring molecules have been examined as chemical tools to target metal鈥揂尾 species, modulate the interaction between the metal and A尾, and subsequently redirect their aggregation into nontoxic, off-pathway unstructured aggregates. These ligands are also capable of attenuating the generation of redox active metal鈥揂尾-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尾. This approach affords compounds with the simultaneous ability to chelate metal ions and interact with A尾. Natural products capable of A尾 interaction have been investigated for their influence on metal-induced A尾 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尾/metal鈥揂尾 interactions, and inhibition of A尾/metal鈥揂尾 reactivity (i.e., aggregation modes of A尾/metal鈥揂尾; 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鈥揂尾 species transforming their size/conformation distribution. The aptitude of these molecules to impact metal鈥揂尾 aggregation pathways, either via inhibition of A尾 aggregate formation, most importantly of oligomers, or disaggregation of preformed fibrils, could originate from their formation of complexes with metal鈥揂尾. Potentially, these molecules could direct metal鈥揂尾 size/conformational states into alternative nontoxic unstructured oligomers, and control the geometry at the A尾-ligated metal center for limited ROS formation to lessen the overall toxicity induced by metal鈥揂尾. Complexation between small molecules and A尾/metal鈥揂尾 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尾-/metal鈥揂尾-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鈥揂尾 complexes, to advance our understanding of their relation to AD pathology.
The development of a cure for Alzheimer鈥檚 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-尾 (A尾), 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尾 plaques. Metal binding to A尾 (metal鈥揂尾) generates/stabilizes potentially toxic A尾 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尾, metal ions, and toxicity, including oxidative stress via metal鈥揂尾, can lead to a deeper understanding of AD development.
To probe the involvement of metal鈥揂尾 in AD pathogenesis, rationally designed and naturally occurring molecules have been examined as chemical tools to target metal鈥揂尾 species, modulate the interaction between the metal and A尾, and subsequently redirect their aggregation into nontoxic, off-pathway unstructured aggregates. These ligands are also capable of attenuating the generation of redox active metal鈥揂尾-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尾. This approach affords compounds with the simultaneous ability to chelate metal ions and interact with A尾. Natural products capable of A尾 interaction have been investigated for their influence on metal-induced A尾 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尾/metal鈥揂尾 interactions, and inhibition of A尾/metal鈥揂尾 reactivity (i.e., aggregation modes of A尾/metal鈥揂尾; 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鈥揂尾 species transforming their size/conformation distribution. The aptitude of these molecules to impact metal鈥揂尾 aggregation pathways, either via inhibition of A尾 aggregate formation, most importantly of oligomers, or disaggregation of preformed fibrils, could originate from their formation of complexes with metal鈥揂尾. Potentially, these molecules could direct metal鈥揂尾 size/conformational states into alternative nontoxic unstructured oligomers, and control the geometry at the A尾-ligated metal center for limited ROS formation to lessen the overall toxicity induced by metal鈥揂尾. Complexation between small molecules and A尾/metal鈥揂尾 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尾-/metal鈥揂尾-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鈥揂尾 complexes, to advance our understanding of their relation to AD pathology.