NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology.
NRF2 deficiency replicates transcriptomic changes in Alzheimer's patients and worsens APP and TAU pathology.
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DOI：
10.1016/j.redox.2017.07.006
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发表时间：
2017-10
期刊：
影响因子：
11.4
通讯作者：
Cuadrado A
中科院分区：
文献类型：
--
作者：
Rojo AI;Pajares M;Rada P;Nuñez A;Nevado-Holgado AJ;Killik R;Van Leuven F;Ribe E;Lovestone S;Yamamoto M;Cuadrado A
未能将成功的神经保护性临床前数据转化为阿尔茨海默病 (AD) 的临床环境表明，淀粉样蛋白病和 tau 蛋白病单独提供了对疾病的不完整看法。我们在这里测试了转录因子 NRF2 活性丧失导致的额外稳态偏差的相关性，NRF2 是多种应激反应的关键调节因子，其活性随着衰老而下降。转录组分析表明，NRF2-KO 小鼠大脑分别复制了人类衰老和 AD 大脑中最失调的 7 条通路和 10 条通路。然后，我们培育了一只结合了淀粉样蛋白病和 tau 蛋白病、野生型 (AT-NRF2-WT) 或 NRF2 缺陷型 (AT-NRF2-KO) 的小鼠。与 AT-NRF2-WT 小鼠相比，AT-NRF2-KO 大脑中氧化应激和神经炎症标记物增加，不溶性磷酸化 TAU 和 Aβ*56 水平更高。年轻成年 AT-NRF2-KO 小鼠表现出空间学习和记忆缺陷，并降低了穿通通路的长期增强作用。这项研究证明了随着衰老而下降的正常稳态反应（例如 NRF2 活性）在防止蛋白毒性、炎症和氧化应激方面的相关性，并提供了对抗 AD 的新策略。 NRF2 缺失模仿了老年和 AD 患者的许多转录组改变。 NRF2 缺乏会加剧 APP/TAU 诱导的氧化和炎症应激。 NRF2 缺乏会加剧 APP/TAU 诱导的蛋白质病。 NRF2 缺陷会加剧 APP/TAU 引起的认知缺陷。
Failure to translate successful neuroprotective preclinical data to a clinical setting in Alzheimer's disease (AD) indicates that amyloidopathy and tauopathy alone provide an incomplete view of disease. We have tested here the relevance of additional homeostatic deviations that result from loss of activity of transcription factor NRF2, a crucial regulator of multiple stress responses whose activity declines with ageing. A transcriptomic analysis demonstrated that NRF2-KO mouse brains reproduce 7 and 10 of the most dysregulated pathways of human ageing and AD brains, respectively. Then, we generated a mouse that combines amyloidopathy and tauopathy with either wild type (AT-NRF2-WT) or NRF2-deficiency (AT-NRF2-KO). AT-NRF2-KO brains presented increased markers of oxidative stress and neuroinflammation as well as higher levels of insoluble phosphorylated-TAU and Aβ*56 compared to AT-NRF2-WT mice. Young adult AT-NRF2-KO mice exhibited deficits in spatial learning and memory and reduced long term potentiation in the perforant pathway. This study demonstrates the relevance of normal homeostatic responses that decline with ageing, such as NRF2 activity, in the protection against proteotoxic, inflammatory and oxidative stress and provide a new strategy to fight AD. NRF2-lack mimics many transcriptomic alterations of elderly and AD patients. APP/TAU-induced oxidative and inflammatory stress is exacerbated by NRF2-deficiency. APP/TAU-induced proteinopathy is exacerbated by NRF2-deficiency. APP/TAU-induced deficits in cognition are aggravated by NRF2-deficiency.
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影响因子：
4.6
作者：
Dutta S;Roy S;Polavaram NS;Baretton GB;Muders MH;Batra S;Datta K
通讯作者：
Datta K
影响因子：
6.1
作者：
Crespo-Biel, Natalia;Theunis, Clara;Van Leuven, Fred
通讯作者：
Van Leuven, Fred
影响因子：
16.6
作者：
Jo, Chulman;Gundemir, Soner;Pritchard, Susanne;Jin, Youngnam N.;Rahman, Irfan;Johnson, Gail V. W.
通讯作者：
Johnson, Gail V. W.
DOI：
10.1006/bbrc.1997.6943
发表时间：
1997-07-18
影响因子：
3.1
作者：
Itoh, K;Chiba, T;Nabeshima, Y
通讯作者：
Nabeshima, Y
影响因子：
4.7
作者：
Gabbita, SP;Lovell, MA;Markesbery, WR
通讯作者：
Markesbery, WR