Enhanced defense against ferroptosis ameliorates cognitive impairment and reduces neurodegeneration in 5xFAD mice.
Enhanced defense against ferroptosis ameliorates cognitive impairment and reduces neurodegeneration in 5xFAD mice.
复制标题
DOI：
10.1016/j.freeradbiomed.2022.01.002
复制
发表时间：
2022-02-20
影响因子：
7.4
通讯作者：
Ran Q
中科院分区：
文献类型：
--
作者：
Chen L;Dar NJ;Na R;McLane KD;Yoo K;Han X;Ran Q
包括脂质过氧化在内的氧化损伤在阿尔茨海默病（AD）中被广泛报道，膜中磷脂的过氧化是铁死亡的驱动因素，铁死亡是一种铁依赖的氧化形式的细胞死亡。然而，铁下垂在AD中的重要性尚不清楚。本研究测试了铁下垂抑制是否能改善AD。5xFAD小鼠是一种广泛使用的AD小鼠认知障碍和强大的神经退行性变模型，其表现出的铁下沉标志物包括脂质过氧化增加、溶磷脂升高和Gpx4水平降低，Gpx4是铁下沉的主要防御者。为了确定对铁下垂的增强防御是否会延缓疾病的发展，我们产生了过表达Gpx4的5xFAD小鼠，即5xFAD/ Gpx4小鼠。与增强对铁下垂的防御一致，5xFAD/GPX4小鼠的神经元显示出减少脂质活性氧的能力增强。此外，与对照组5xFAD小鼠相比，5xFAD/GPX4小鼠的学习和记忆能力显著提高，神经退行性变减少。此外，5xFAD/GPX4小鼠的铁下垂标记物减弱。我们的研究结果表明，增强对铁下垂的防御可以有效改善5xFAD小鼠的认知障碍和减少神经退行性变。这些发现支持了铁下垂是AD发病机制的关键因素的观点。
Oxidative damage including lipid peroxidation is widely reported in Alzheimer’s disease (AD) with the peroxidation of phospholipids in membranes being the driver of ferroptosis, an iron-dependent oxidative form of cell death. However, the importance of ferroptosis in AD remains unclear. This study tested whether ferroptosis inhibition ameliorates AD. 5xFAD mice, a widely used AD mouse model with cognitive impairment and robust neurodegeneration, exhibit markers of ferroptosis including increased lipid peroxidation, elevated lyso-phospholipids, and reduced level of Gpx4, the master defender against ferroptosis. To determine if enhanced defense against ferroptosis retards disease development, we generated 5xFAD mice that overexpress Gpx4, i.e., 5xFAD/GPX4 mice. Consistent with enhanced defense against ferroptosis, neurons from 5xFAD/GPX4 mice showed an augmented capacity to reduce lipid reactive oxygen species. In addition, compared with control 5xFAD mice, 5xFAD/GPX4 mice showed significantly improved learning and memory abilities and had reduced neurodegeneration. Moreover, 5xFAD/GPX4 mice exhibited attenuated markers of ferroptosis. Our results indicate that enhanced defense against ferroptosis is effective in ameliorating cognitive impairment and decreasing neurodegeneration of 5xFAD mice. The findings support the notion that ferroptosis is a key contributor to AD pathogenesis.
登录
查看更多内容
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
5.8
作者：
Grimm, M. O. W.;Stahlmann, C. P.;Hartmann, T.
通讯作者：
Hartmann, T.
影响因子：
4.2
作者：
Lovell, MA;Ehmann, WD;Markesbery, WR
通讯作者：
Markesbery, WR
影响因子：
3.5
作者：
Girard, Stephane D.;Jacquet, Marlyse;Marchetti, Evelyne
通讯作者：
Marchetti, Evelyne
影响因子：
2.9
作者：
Koppaka, V;Axelsen, PH
通讯作者：
Axelsen, PH