Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease
Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease
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DOI：
10.1073/pnas.1001422107
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发表时间：
2010-04-06
影响因子：
11.1
通讯作者：
Brinton, Roberta Diaz
中科院分区：
文献类型：
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作者：
Wang, Jun Ming;Singh, Chanpreet;Brinton, Roberta Diaz
我们先前的分析表明，别孕酮(APα)在体外显著促进啮齿动物和人类神经前体细胞的增殖。在这项研究中，我们研究了APα对3月龄雄性三重转基因阿尔茨海默病(3xTgAD)小鼠海马区(SGZ)神经发生的促进作用，以及APα诱导的神经前体细胞存活与3xTgAD小鼠记忆功能的相关性。BrdU掺入无偏体视学分析测定神经前体细胞的增殖，流式细胞仪测定BrdU+细胞的存活率。学习和记忆功能的评估使用海马区依赖的跟踪眨眼条件反射范式。3个月时，3xTgAD组小鼠SGZ中BrdU+细胞的基础水平明显低于非TG组小鼠，尽管缺乏明显的AD病理。APα以剂量依赖的方式显著增加3xTgAD小鼠SGZ中BrdU+细胞的数量，并使SGZ的增殖恢复到正常水平。与增殖缺陷一样，3xTgAD小鼠也表现出学习和记忆缺陷。APα逆转认知缺陷，将学习和记忆能力恢复到正常非甘油三酯小鼠的水平。在3xTgAD小鼠中，APα诱导的神经前体细胞存活与APα诱导的记忆表现显著相关。这些发现表明，在免疫可检测到Aβ之前明显的早期神经源性缺陷可能与AD的认知表型有关，APα可能作为一种再生疗法来预防或延迟与轻度认知障碍和阿尔茨海默病相关的神经源性和认知缺陷。
Our previous analyses showed that allopregnanolone (AP alpha) significantly increased proliferation of rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of AP alpha to promote neurogenesis in the hippocampal subgranular zone (SGZ), to reverse learning and memory deficits in 3-month-old male triple transgenic mouse model of Alzheimer's (3xTgAD) and the correlation between AP alpha-induced neural progenitor cell survival and memory function in 3xTgAD mice. Neural progenitor cell proliferation was determined by unbiased stereological analysis of BrdU incorporation and survival determined by FACS for BrdU+ cells. Learning and memory function was assessed using the hippocampal-dependent trace eye-blink conditioning paradigm. At 3 months, basal level of BrdU+ cells in the SGZ of 3xTgAD mice was significantly lower relative to non-Tg mice, despite the lack of evident AD pathology. AP alpha significantly increased, in a dose-dependent manner, BrdU+ cells in SGZ in 3xTgAD mice and restored SGZ proliferation to normal magnitude. As with the deficit in proliferation, 3xTgAD mice exhibited deficits in learning and memory. AP alpha reversed the cognitive deficits to restore learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, AP alpha-induced survival of neural progenitors was significantly correlated with AP alpha-induced memory performance. These findings suggest that early neurogenic deficits, which were evident before immunodetectable A beta, may contribute to the cognitive phenotype of AD, and that AP alpha could serve as a regenerative therapeutic to prevent or delay neurogenic and cognitive deficits associated with mild cognitive impairment and Alzheimer's disease.