Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease.
Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease.
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DOI：
10.1111/jnc.12059
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发表时间：
2013-01
影响因子：
4.7
通讯作者：
Bosetti F
中科院分区：
文献类型：
--
作者：
Choi SH;Aid S;Caracciolo L;Minami SS;Niikura T;Matsuoka Y;Turner RS;Mattson MP;Bosetti F
一些流行病学和临床前研究表明，非甾体抗炎药（NSAID）可抑制环氧合酶（考克斯），降低阿尔茨海默病（AD）的风险，并可降低β-淀粉样蛋白（Aβ）的产生和抑制神经炎症。然而，后续的临床试验，主要是使用选择性环氧合酶（考克斯）-2抑制剂，未能显示任何有益的效果，在AD患者的轻度至重度认知缺陷。最近的数据表明，考克斯-1，经典地被视为稳态异构体，定位于小胶质细胞中，并且积极参与由促炎刺激物（包括Aβ、脂多糖和白细胞介素）诱导的脑损伤。我们假设神经炎症对疾病进展至关重要，选择性考克斯-1抑制而非考克斯-2抑制可减少神经炎症和AD病理。在这里，我们表明，治疗20个月大的三重转基因AD（3 × Tg-AD）小鼠与考克斯-1选择性抑制剂SC-560改善空间学习和记忆，并减少淀粉样蛋白沉积和tau蛋白过度磷酸化。SC-560还降低了3 × Tg-AD小鼠的胶质细胞活化和脑炎症标志物的表达，并改变了活化的小胶质细胞表型，促进了其吞噬能力。目前的研究结果首次证明选择性考克斯-1抑制可减少3 × Tg-AD小鼠的神经炎症、神经病理学并改善认知功能。因此，选择性考克斯-1抑制剂应进一步研究作为一种潜在的治疗AD的方法。
Several epidemiological and preclinical studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), reduce the risk of Alzheimer's disease (AD) and can lower β-amyloid (Aβ) production and inhibit neuroinflammation. However, follow-up clinical trials, mostly using selective cyclooxygenase (COX)-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive deficits. Recent data indicated that COX-1, classically viewed as the homeostatic isoform, is localized in microglia and is actively involved in brain injury induced by pro-inflammatory stimuli including Aβ, lipopolysaccharide, and interleukins. We hypothesized that neuroinflammation is critical for disease progression and selective COX-1 inhibition, rather than COX-2 inhibition, can reduce neuroinflammation and AD pathology. Here, we show that treatment of 20-month-old triple transgenic AD (3 × Tg-AD) mice with the COX-1 selective inhibitor SC-560 improved spatial learning and memory, and reduced amyloid deposits and tau hyperphosphorylation. SC-560 also reduced glial activation and brain expression of inflammatory markers in 3 × Tg-AD mice, and switched the activated microglia phenotype promoting their phagocytic ability. The present findings are the first to demonstrate that selective COX-1 inhibition reduces neuroinflammation, neuropathology, and improves cognitive function in 3 × Tg-AD mice. Thus, selective COX-1 inhibition should be further investigated as a potential therapeutic approach for AD.
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影响因子：
6.1
作者：
Coma M;Serenó L;Da Rocha-Souto B;Scotton TC;España J;Sánchez MB;Rodríguez M;Agulló J;Guardia-Laguarta C;Garcia-Alloza M;Borrelli LA;Clarimón J;Lleó A;Bacskai BJ;Saura CA;Hyman BT;Gómez-Isla T
通讯作者：
Gómez-Isla T
影响因子：
5.3
作者：
Hickman, Suzanne E.;Allison, Elizabeth K.;El Khoury, Joseph
通讯作者：
El Khoury, Joseph
DOI：
10.18632/aging.100021
发表时间：
2009-02-11
期刊：
Aging
影响因子：
--
作者：
Choi SH;Bosetti F
通讯作者：
Bosetti F
DOI：
10.1016/j.jalz.2010.12.014
发表时间：
2011-07
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Breitner JC;Baker LD;Montine TJ;Meinert CL;Lyketsos CG;Ashe KH;Brandt J;Craft S;Evans DE;Green RC;Ismail MS;Martin BK;Mullan MJ;Sabbagh M;Tariot PN;ADAPT Research Group
通讯作者：
ADAPT Research Group
影响因子：
5.3
作者：
Jimenez, Sebastian;Baglietto-Vargas, David;Vitorica, Javier
通讯作者：
Vitorica, Javier