Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, USA.
Curr Alzheimer Res. 2011 Jun;8(4):385-92. doi: 10.2174/156720511795745285.
Amyloid beta (Aβ) peptides are related to the pathogenesis of Alzheimer's disease (AD). The search for therapeutic strategies that lower these peptides has mainly focused on the proteolytic processing of the β-amyloid precursor protein (APP), and other post-transcriptional pathways. The transcription factor specificity protein 1 (Sp1) is vital for the regulation of several genes involved in AD including APP and the beta site APP cleaving enzyme 1 (BACE1). We have previously reported that tolfenamic acid promotes the degradation of Sp1 protein (SP1) in pancreatic human cancer cells and mice tumors. This study examines the ability of tolfenamic acid to reduce SP1 levels, and thereby decrease APP transcription and Aβ levels in rodent brains. Tolfenamic acid was administered by oral gavage to C57BL/6 mice at variable dosages and for different time periods. Results have shown that tolfenamic acid was able to down regulate brain protein levels of SP1, APP, and Aβ. These findings demonstrate that interference with upstream transcriptional pathways can lower pathogenic intermediates associated with AD, and thus tolfenamic acid represents a novel approach for the development of a therapeutic intervention for AD.
淀粉样蛋白β（Aβ）肽与阿尔茨海默病（AD）的发病机制有关。寻找降低这些肽的治疗策略主要集中在β-淀粉样前体蛋白（APP）的蛋白水解加工和其他转录后途径上。转录因子特异性蛋白 1（Sp1）对于调节包括 APP 和β位淀粉样前体蛋白裂解酶 1（BACE1）在内的几种与 AD 相关的基因至关重要。我们之前的研究报告表明，托芬那酸可促进胰腺人类癌细胞和小鼠肿瘤中 Sp1 蛋白（SP1）的降解。本研究检查了托芬那酸降低 SP1 水平的能力，从而降低啮齿动物大脑中的 APP 转录和 Aβ 水平。托芬那酸通过口服灌胃给予 C57BL/6 小鼠不同剂量和不同时间。结果表明，托芬那酸能够下调大脑中 SP1、APP 和 Aβ 的蛋白水平。这些发现表明，干扰上游转录途径可以降低与 AD 相关的致病中间体，因此托芬那酸代表了开发 AD 治疗干预措施的新方法。
