Increased Amyloid-β Peptide-Induced Memory Deficits in Phospholipid Transfer Protein (PLTP) Gene Knockout Mice
Increased Amyloid-β Peptide-Induced Memory Deficits in Phospholipid Transfer Protein (PLTP) Gene Knockout Mice
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DOI：
10.1038/npp.2012.247
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发表时间：
2013-04-01
影响因子：
7.6
通讯作者：
Maurice, Tangui
中科院分区：
文献类型：
--
作者：
Desrumaux, Catherine;Pisoni, Amandine;Maurice, Tangui
氧化应激被认为是阿尔茨海默病（AD）最早和最强烈的病理过程之一，抗氧化剂维生素E已被证明能有效预防淀粉样斑块的形成和神经退行性变。血浆磷脂转移蛋白（PLTP）在体内维生素E转移中起主要作用，小鼠血浆磷脂转移蛋白缺乏与大脑维生素E水平降低有关。为了确定PLTP对体内淀粉样蛋白病理的影响，我们分析了PLTP缺陷（PLTP- ko）小鼠对脑室内注射寡聚淀粉样蛋白- β (25-35) （A β(25-35)）肽（一种非转基因AD模型）诱导的毒性作用的易感性。在基础条件下，与野生型小鼠相比，PLTP-KO小鼠表现出脑氧化应激增加，脑A β(1-42)水平升高，突触功能标志物synaptophysin表达降低。这种PLTP-KO表型与注射A β(25-35)肽1周后记忆损伤增加有关。通过长期膳食补充恢复PLTP-KO小鼠脑维生素E水平，可防止a β(25-35)诱导的记忆缺陷，减少脑氧化应激和毒性。我们得出结论，PLTP通过其向大脑输送维生素E的能力，构成了一种内源性神经保护剂。提高PLTP活性可能为开发神经保护疗法提供新的途径。神经精神药理学杂志，2013,38,817-825；doi: 10.1038 / npp.2012.247;2013年1月16日在线发布
Oxidative stress is recognized as one of the earliest and most intense pathological processes in Alzheimer's disease (AD), and the antioxidant vitamin E has been shown to efficiently prevent amyloid plaque formation and neurodegeneration. Plasma phospholipid transfer protein (PLTP) has a major role in vitamin E transfers in vivo, and PLTP deficiency in mice is associated with reduced brain vitamin E levels. To determine the impact of PLTP on amyloid pathology in vivo, we analyzed the vulnerability of PLTP-deficient (PLTP-KO) mice to the toxic effects induced by intracerebroventricular injection of oligomeric amyloid-beta(25-35) (A beta(25-35)) peptide, a non-transgenic model of AD. Under basal conditions, PLTP-KO mice showed increased cerebral oxidative stress, increased brain A beta(1-42) levels, and a lower expression of the synaptic function marker synaptophysin, as compared with wild-type mice. This PLTP-KO phenotype was associated with increased memory impairment 1 week after A beta(25-35) peptide injection. Restoration of brain vitamin E levels in PLTP-KO mice through a chronic dietary supplementation prevented A beta(25-35)-induced memory deficits and reduced cerebral oxidative stress and toxicity. We conclude that PLTP, through its ability to deliver vitamin E to the brain, constitutes an endogenous neuroprotective agent. Increasing PLTP activity may offer a new way to develop neuroprotective therapies. Neuropsychopharmacology (2013) 38, 817-825; doi:10.1038/npp.2012.247; published online 16 January 2013