Allopregnanolone promotes regeneration and reduces β-amyloid burden in a preclinical model of Alzheimer's disease.
Allopregnanolone promotes regeneration and reduces β-amyloid burden in a preclinical model of Alzheimer's disease.
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DOI：
10.1371/journal.pone.0024293
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Brinton RD
中科院分区：
文献类型：
--
作者：
Chen S;Wang JM;Irwin RW;Yao J;Liu L;Brinton RD
在此之前，我们已经证明别孕酮(AP-α)在体外可以促进啮齿动物和人类神经前体细胞的增殖。进一步，我们证明了APα促进了阿尔茨海默病雄性三重转基因小鼠(3xTgAD)海马区颗粒下区神经发生，并逆转了学习和记忆障碍。在目前的研究中，我们在3xTgAD雄性小鼠模型中确定了APα在促进新生神经细胞存活的同时减少阿尔茨海默病(AD)病理的有效性。3种不同的APα治疗方案的比较分析表明，APα每周1次，连续6个月，在促进神经发生和新生细胞存活的同时，减轻AD的病理程度是最有效的。我们进一步研究了APα对Aβ负荷的影响。治疗是在神经元内Aβ蓄积之前或之后开始的。结果表明，AP-α1周给药6个月可显著提高新生神经元存活率，同时减轻A-β病理改变，以病理前治疗组疗效最好。APα显著减少了海马区、皮质和杏仁体中Aβ的生成，这与Aβ结合酒精脱氢酶的表达减少是平行的。此外，APα显著降低了小胶质细胞的活性，表现为减少了OX42的表达，而增加了少突胶质细胞髓鞘标志物CNPase的表达。机制分析表明，APα在病理前治疗增加了肝脏X受体、孕烷X受体和3-羟基-3-甲基-戊二酰辅酶A还原酶(HMG-CoA-R)的表达，这三种蛋白质调节胆固醇的稳态和脑内清除。总之，这些发现为APα的最佳治疗方案提供了临床前证据，以实现作为一种疾病修改治疗方案的疗效，以促进再生，同时减少与阿尔茨海默病相关的病理。
Previously, we demonstrated that allopregnanolone (APα) promoted proliferation of rodent and human neural progenitor cells in vitro. Further, we demonstrated that APα promoted neurogenesis in the hippocampal subgranular zone (SGZ) and reversed learning and memory deficits in the male triple transgenic mouse model of Alzheimer's (3xTgAD). In the current study, we determined the efficacy of APα to promote the survival of newly generated neural cells while simultaneously reducing Alzheimer's disease (AD) pathology in the 3xTgAD male mouse model. Comparative analyses between three different APα treatment regimens indicated that APα administered 1/week for 6 months was maximally efficacious for simultaneous promotion of neurogenesis and survival of newly generated cells and reduction of AD pathology. We further investigated the efficacy of APα to impact Aβ burden. Treatment was initiated either prior to or post intraneuronal Aβ accumulation. Results indicated that APα administered 1/week for 6 months significantly increased survival of newly generated neurons and simultaneously reduced Aβ pathology with greatest efficacy in the pre-pathology treatment group. APα significantly reduced Aβ generation in hippocampus, cortex, and amygdala, which was paralleled by decreased expression of Aβ-binding-alcohol-dehydrogenase. In addition, APα significantly reduced microglia activation as indicated by reduced expression of OX42 while increasing CNPase, an oligodendrocyte myelin marker. Mechanistic analyses indicated that pre-pathology treatment with APα increased expression of liver-X-receptor, pregnane-X-receptor, and 3-hydroxy-3-methyl-glutaryl-CoA-reductase (HMG-CoA-R), three proteins that regulate cholesterol homeostasis and clearance from brain. Together these findings provide preclinical evidence for the optimal treatment regimen of APα to achieve efficacy as a disease modifying therapeutic to promote regeneration while simultaneously decreasing the pathology associated with Alzheimer's disease.
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影响因子：
4.2
作者：
Bartzokis, George;Lu, Po H.;Tingus, Kathleen;Mendez, Mario F.;Richard, Aurore;Peters, Douglas G.;Oluwadara, Bolanle;Barrall, Katherine A.;Finn, J. Paul;Villablanca, Pablo;Thompson, Paul M.;Mintz, Jim
通讯作者：
Mintz, Jim
DOI：
10.1016/j.jalz.2009.04.1228
发表时间：
2010-01
期刊：
Alzheimer's & dementia : the journal of the Alzheimer's Association
影响因子：
--
作者：
Kuczynski B;Targan E;Madison C;Weiner M;Zhang Y;Reed B;Chui HC;Jagust W
通讯作者：
Jagust W
DOI：
10.1073/pnas.95.11.6448
发表时间：
1998-05-26
影响因子：
11.1
作者：
Lambert, MP;Barlow, AK;Klein, WL
通讯作者：
Klein, WL
影响因子：
3.2
作者：
Ahmed, Zeshan;Shaw, Gerry;Dickson, Dennis W.
通讯作者：
Dickson, Dennis W.
影响因子：
10.6
作者：
Marx, Christine E.;Trost, William T.;Lieberman, Jeffrey A.
通讯作者：
Lieberman, Jeffrey A.