Nanoparticle-chelator conjugates as inhibitors of amyloid-beta aggregation and neurotoxicity: a novel therapeutic approach for Alzheimer disease.
Nanoparticle-chelator conjugates as inhibitors of amyloid-beta aggregation and neurotoxicity: a novel therapeutic approach for Alzheimer disease.
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DOI：
10.1016/j.neulet.2009.03.064
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发表时间：
2009-05-22
影响因子：
2.5
通讯作者：
Smith MA
中科院分区：
文献类型：
--
作者：
Liu G;Men P;Kudo W;Perry G;Smith MA
氧化应激和β淀粉样蛋白被认为是阿尔茨海默病（AD）神经退行性变发生和发展的主要病因和病理因素。由于这种氧化应激的原因，在AD患者的脑中以高浓度发现并在病理损伤中特异性地积累的过渡金属如铁和铜被认为是改变氧化还原状态的关键贡献者。同样，淀粉样蛋白-β的聚集和毒性取决于过渡金属。因此，选择性结合并去除和/或“氧化还原沉默”过渡金属的螯合剂长期以来被认为是AD的有吸引力的治疗靶标。然而，许多传统金属螯合剂的血脑屏障和神经毒性限制了它们在AD或其他神经退行性疾病中的应用。为了避免这一点，我们以前提出，与铁螯合剂缀合的纳米颗粒可能有潜力将螯合剂递送到大脑中，并克服螯合剂的生物利用度和毒副作用等问题。在这项研究中，我们合成了一种原型纳米颗粒-螯合剂缀合物（Nano-N2 PY），并证明了其保护人类皮质神经元免受淀粉样蛋白-β相关氧化毒性的能力。此外，Nano-N2 PY纳米颗粒-螯合剂缀合物有效地抑制淀粉样蛋白-β聚集体的形成。总的来说，这项研究表明，纳米N2 PY，或其他纳米粒子共轭金属螯合剂，可以提供一种新的治疗策略，AD和其他神经退行性疾病与过量的过渡金属。
Oxidative stress and amyloid-β are considered major etiological and pathological factors in the initiation and promotion of neurodegeneration in Alzheimer disease (AD). Insomuch as causes of such oxidative stress, transition metals, such as iron and copper, which are found in high concentrations in the brains of AD patients and accumulate specifically in the pathological lesions, are viewed as key contributors to the altered redox state. Likewise, the aggregation and toxicity of amyloid-β is dependent upon transition metals. As such, chelating agents that selectively bind to and remove and/or “redox silence” transition metals have long been considered an attractive therapeutic target for AD. However, the blood-brain barrier and neurotoxicity of many traditional metal chelators has limited their utility in AD or other neurodegenerative disorders. To circumvent this, we previously suggested that nanoparticles conjugated to iron chelators may have the potential to deliver chelators into the brain and overcome such issues as chelator bioavailability and toxic side-effects. In this study, we synthesized a prototype nanoparticle-chelator conjugate (Nano-N2PY) and demonstrated its ability to protect human cortical neurons from amyloid-β-associated oxidative toxicity. Furthermore, Nano-N2PY nanoparticle-chelator conjugates effectively inhibited amyloid-β aggregate formation. Overall, this study indicates that Nano-N2PY, or other nanoparticles conjugated to metal chelators, may provide a novel therapeutic strategy for AD and other neurodegenerative diseases associated with excess transition metals.
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影响因子：
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