Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer's disease
Genetic reduction of Nrf2 exacerbates cognitive deficits in a mouse model of Alzheimer's disease
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DOI：
10.1093/hmg/ddx361
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发表时间：
2017-12-15
影响因子：
3.5
通讯作者：
Oddo, Salvatore
中科院分区：
文献类型：
--
作者：
Branca, Caterina;Ferreira, Eric;Oddo, Salvatore
衰老是多种神经退行性疾病的主要危险因素，包括阿尔茨海默病（AD）。然而，衰老导致神经退行性变的机制仍然难以捉摸。核因子（红细胞衍生 2）样 2 (Nrf2) 是一种转录因子，通过与抗氧化反应元件结合来调节大量基因的表达。 Nrf2 水平随着年龄的增长而降低，据报道，在死后的人类大脑和 AD 动物模型中 Nrf2 水平降低。然而，目前尚不清楚 Nrf2 是否在 AD 相关认知缺陷中发挥作用。为了解决这个问题，我们使用遗传方法从 APP/PS1 小鼠（一种广泛使用的 AD 动物模型）中去除 Nrf2 基因。我们发现 Nrf2 的缺乏会显着加剧 APP/PS1 的认知缺陷，但不会改变粗大运动功能。具体来说，我们发现空间学习和记忆以及工作和联想记忆的缺陷加剧。不同的大脑区域控制这些行为测试，表明 Nrf2 的缺乏对大脑功能具有全局影响。认知的变化与 Aβ 和干扰素γ (IFNγ) 水平的增加以及小神经胶质细胞增生有关。 IFN γ 水平的变化值得注意，因为之前发表的证据表明 IFN γ 可以增加小胶质细胞的激活并诱导 Aβ 的产生。我们的数据表明 Nrf2 和 AD 介导的认知能力下降之间存在明显联系，并进一步加强了 Nrf2 和 AD 之间的联系。
Aging is the major risk factor for several neurodegenerative diseases, including Alzheimer's disease (AD). However, the mechanisms by which aging contributes to neurodegeneration remain elusive. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a transcription factor that regulates expression of a vast number of genes by binding to the antioxidant response element. Nrf2 levels decrease as a function of age, and reduced Nrf2 levels have been reported in postmortem human brains and animal models of AD. Nevertheless, it is still unknown whether Nrf2 plays a role in the cognitive deficits associated with AD. To address this question, we used a genetic approach to remove the Nrf2 gene from APP/PS1 mice, a widely used animal model of AD. We found that the lack of Nrf2 significantly exacerbates cognitive deficits in APP/PS1, without altering gross motor function. Specifically, we found an exacerbation of deficits in spatial learning and memory, as well as in working and associative memory. Different brain regions control these behavioral tests, indicating that the lack of Nrf2 has a global effect on brain function. The changes in cognition were linked to an increase in A beta and interferon-gamma (IFN gamma ) levels, and microgliosis. The changes in IFN gamma levels are noteworthy as previously published evidence indicates that IFN gamma can increase microglia activation and induce A beta production. Our data suggest a clear link between Nrf2 and AD-mediated cognitive decline and further strengthen the connection between Nrf2 and AD.