We previously demonstrated that allopregnanolone (APα) increased proliferation of neural progenitor cells and reversed neurogenic and cognitive deficits prior to Alzheimer's disease (AD) pathology (Wang, J.M., Johnston, P.B., Ball, B.G., Brinton, R.D., 2005. The neurosteroid allopregnanolone promotes proliferation of rodent and human neural progenitor cells and regulates cell-cycle gene and protein expression. J. Neurosci. 25, 4706-4718; Wang, J.M., Singh, C., Liu, L., Irwin, R.W., Chen, S., Chung, E.J., Thompson, R.F., Brinton, R.D., 2010. Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. U. S. A. 107, 6498-6503). Herein, we determined efficacy of APα to restore neural progenitor cell survival and associative learning and memory subsequent to AD pathology in male 3xTgAD mice and their nontransgenic (nonTg) counterparts. APα significantly increased survival of bromodeoxyuridine positive (BrdU+) cells and hippocampal-dependent associative learning and memory in 3xTgAD mice in the presence of intraneuronal amyloid beta (Aβ) whereas APα was ineffective subsequent to development of extraneuronal Aβ plaques. Restoration of hippocampal-dependent associative learning was maximal by the first day and sustained throughout behavioral training. Learning and memory function in APα-treated 3xTgAD mice was 100% greater than vehicle-treated and comparable to maximal normal nonTg performance. In aged 15-month-old nonTg mice, APα significantly increased survival of bromodeoxyuridine-positive cells and hippocampal-dependent associative learning and memory. Results provide preclinical evidence that APα promoted survival of newly generated cells and restored cognitive performance in the preplaque phase of AD pathology and in late-stage normal aging.

译文

我们先前证明了在阿尔茨海默氏病 (AD) 病理之前,allopregnanolone (ap α) 增加了神经祖细胞的增殖并逆转了神经源性和认知缺陷 (Wang,J.M.,Johnston,P.B.,Ball,b.g.,Brinton,R.D.,2005.神经甾体异戊二醇酮促进啮齿动物和人神经祖细胞的增殖,并调节细胞周期基因和蛋白质的表达。J. Neurosci。25,4706-4718; Wang,j.m.,Singh,C.,Liu,L.,Irwin,R.W.,Chen,S.,Chung,E.J.,Thompson,R.F.,Brinton,R.D.,2010。Allopregnanolone逆转阿尔茨海默氏病小鼠模型中的神经源性和认知缺陷。Proc. Natl. Acad. Sci.美国107,6498-6503)。在本文中,我们确定了ap α 在雄性3xtgad小鼠及其非转基因 (nonTg) 对应物中恢复神经祖细胞存活以及AD病理后的联想学习和记忆的功效。在存在神经内淀粉样蛋白 β (a β) 的情况下,APα 显着增加了3xtgad小鼠的溴脱氧尿苷阳性 (BrdU) 细胞和海马依赖性联想学习和记忆,而APα 在神经外a β 斑块形成后无效。海马依赖性联想学习的恢复在第一天达到最大,并在整个行为训练中持续。在APα 处理的3xtgad小鼠中,学习和记忆功能100% 大于赋形剂处理的小鼠,并且与最大正常非tg表现相当。在15个月大的nonTg小鼠中,ap α 显着提高了溴脱氧尿苷阳性细胞和海马依赖性联想学习和记忆的存活率。结果提供了临床前证据,表明ap α 促进了新生细胞的存活,并在AD病理的斑块前期和正常衰老后期恢复了认知能力。

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