Ferulic acid is a nutraceutical β-secretase modulator that improves behavioral impairment and alzheimer-like pathology in transgenic mice.
Ferulic acid is a nutraceutical β-secretase modulator that improves behavioral impairment and alzheimer-like pathology in transgenic mice.
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DOI：
10.1371/journal.pone.0055774
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Town T
中科院分区：
文献类型：
--
作者：
Mori T;Koyama N;Guillot-Sestier MV;Tan J;Town T
在阿尔茨海默病（AD）患者的大脑中，淀粉样蛋白前体蛋白（APP）蛋白水解是产生淀粉样蛋白-β (Aβ)肽所必需的，这些肽构成了β-淀粉样蛋白斑块。近年来，人们对从植物中提取的一组抗淀粉样蛋白化合物对阿尔茨海默病的治疗产生了兴趣。我们给转基因papp小鼠脑淀粉样变性模型（携带突变型人类APP和早老素-1转基因）口服脑渗透小分子酚类化合物阿威酸（FA），并评估行为损害和ad样病理。口服FA治疗6个月逆转了转基因相关的行为缺陷，包括多动症、物体识别、空间工作和参考记忆缺陷，但没有改变野生型小鼠的行为。此外，fa处理的papp小鼠脑实质和脑血管β-淀粉样蛋白沉积以及各种Aβ物种（包括低聚物）的丰度降低。这些作用发生在β-羧基端APP片段的切割减少，β-位点APP切割酶1蛋白的稳定性和活性降低，神经炎症减轻，氧化应激稳定。作为体外验证，我们用FA处理了特征明确的突变型人APP过表达的小鼠神经元样细胞，发现Aβ产量显著降低，淀粉样变性APP蛋白水解减少。总之，这些结果强调FA是一种β分泌酶调节剂，具有治疗AD的潜力。
Amyloid precursor protein (APP) proteolysis is required for production of amyloid-β (Aβ) peptides that comprise β-amyloid plaques in brains of Alzheimer’s disease (AD) patients. Recent AD therapeutic interest has been directed toward a group of anti-amyloidogenic compounds extracted from plants. We orally administered the brain penetrant, small molecule phenolic compound ferulic acid (FA) to the transgenic PSAPP mouse model of cerebral amyloidosis (bearing mutant human APP and presenilin-1 transgenes) and evaluated behavioral impairment and AD-like pathology. Oral FA treatment for 6 months reversed transgene-associated behavioral deficits including defective: hyperactivity, object recognition, and spatial working and reference memory, but did not alter wild-type mouse behavior. Furthermore, brain parenchymal and cerebral vascular β-amyloid deposits as well as abundance of various Aβ species including oligomers were decreased in FA-treated PSAPP mice. These effects occurred with decreased cleavage of the β-carboxyl-terminal APP fragment, reduced β-site APP cleaving enzyme 1 protein stability and activity, attenuated neuroinflammation, and stabilized oxidative stress. As in vitro validation, we treated well-characterized mutant human APP-overexpressing murine neuron-like cells with FA and found significantly decreased Aβ production and reduced amyloidogenic APP proteolysis. Collectively, these results highlight that FA is a β-secretase modulator with therapeutic potential against AD.
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DOI：
10.1073/pnas.0500195102
发表时间：
2005-03-08
影响因子：
11.1
作者：
De Rosa, R;Garcia, AA;Cattaneo, A
通讯作者：
Cattaneo, A
影响因子：
4.2
作者：
Benzing, WC;Wujek, JR;Brunden, KR
通讯作者：
Brunden, KR
影响因子：
2.9
作者：
Cheng, Chin-Yi;Su, Shan-Yu;Hsieh, Ching-Liang
通讯作者：
Hsieh, Ching-Liang
影响因子：
7.8
作者：
Goldsbury, Claire;Whiteman, Ineka T.;Lim, Yun-An
通讯作者：
Lim, Yun-An
影响因子：
15.8
作者：
Jankowsky JL;Slunt HH;Gonzales V;Savonenko AV;Wen JC;Jenkins NA;Copeland NG;Younkin LH;Lester HA;Younkin SG;Borchelt DR
通讯作者：
Borchelt DR