Novel drug targets based on metallobiology of Alzheimer's disease.
Novel drug targets based on metallobiology of Alzheimer's disease.
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DOI：
10.1517/14728222.2010.525352
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发表时间：
2010-11
影响因子：
5.8
通讯作者：
Rogers JT
中科院分区：
文献类型：
--
作者：
Bandyopadhyay S;Huang X;Lahiri DK;Rogers JT
老年斑中锌、铁、铜和铝的增加加重了β淀粉样蛋白（Aβ）介导的氧化损伤，并在阿尔茨海默病（AD）中充当Aβ聚集的催化剂。因此，通过螯合疗法破坏异常的金属-肽相互作用作为对抗阿尔茨海默氏淀粉样蛋白发病机制的合理治疗策略具有相当大的前景。综述了金属诱导SP成因的复杂性。金属螯合剂的分子作用机制的最新进展进行了讨论，其潜在的成为药物的关键评估。考虑到金属与阿尔茨海默氏症淀粉样前体蛋白（APP）上的金属反应元件的相互作用，读者将了解在开发AD治疗剂的筛选活动时需要记住的几点。在APP转录本的5′非翻译区（UTR）中的功能性铁响应元件（IRE）RNA茎环调节神经APP翻译。去铁胺、氯碘羟喹、四硫羟喹、二巯基丙醇、VK-28和天然抗氧化剂，如姜黄素和银杏叶需要作为AD治疗剂进行关键评价。有必要进行新的筛选（与金属生物学相关），以确定有效的治疗AD的药物。
Increased localization of Zn, Fe, Cu and Al within the senile plaques (SP) exacerbates amyloid beta (Aβ)-mediated oxidative damage, and acts as catalyst for Aβ aggregation in Alzheimer’s disease (AD). Thus, disruption of aberrant metal-peptide interactions via chelation therapy holds considerable promise as a rational therapeutic strategy against Alzheimer’s amyloid pathogenesis. The complexities of metal-induced genesis of SP are reviewed. The recent advances in the molecular mechanism of action of metal chelating agents are discussed with critical assessment of their potential to become drugs. Taking into consideration the interaction of metals with the metal-responsive elements on the Alzheimer’s amyloid precursor protein (APP), readers will gain understanding of several points to bear in mind when developing a screening campaign for AD-therapeutics. A functional iron-responsive element (IRE) RNA stem loop in the 5′ untranslated region (UTR) of the APP transcript regulates neural APP translation. Desferrioxamine, clioquinol, tetrathiolmolybdate, dimercaptopropanol, VK-28 and natural antioxidants, such as curcumin and ginko biloba need critical evaluation as AD therapeutics. There is a necessity for novel screens (related to metallobiology) to identify therapeutics effective in AD.