Estrogen restores cognition and cholinergic phenotype in an animal model of Down syndrome
Estrogen restores cognition and cholinergic phenotype in an animal model of Down syndrome
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DOI：
10.1016/s0031-9384(02)00884-3
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发表时间：
2002-11-01
影响因子：
2.9
通讯作者：
Crnic, LS
中科院分区：
文献类型：
--
作者：
Granholm, ACE;Ford, KA;Crnic, LS
雌激素维持基底前脑（BF）胆碱能神经元的正常功能，因此雌激素替代疗法（ERT）已被提出作为阿尔茨海默病（AD）的治疗方法。我们在唐氏综合征（DS）的动物模型，染色体16节段性三体（Ts 65 Dn）小鼠中提供了支持这一假设的证据。这些小鼠发生与DS和AD患者的年轻成年人相似的胆碱能变性。雌激素替代疗法尚未在DS女性中进行测试，尽管她们比正常女性更有可能发展为早期绝经和AD。雌性Ts 65 Dn和正常小鼠（11-15个月）接受皮下雌激素丸或假手术。60天后，雌激素治疗改善了Ts 65 Dn小鼠T迷宫任务的学习，并使其在逆转任务学习中的行为正常化，这是认知灵活性的一种衡量标准。胆碱乙酰转移酶（ChAT）免疫阳性BF神经元的体视学评价表明，雌激素增加细胞的大小和Ts 65 Dn小鼠内侧隔胆碱能神经元的总数。此外，雌激素增加了三体小鼠BF中的NGF蛋白水平。这些发现支持了新出现的假说，即雌激素可能在神经退行性变和认知能力下降，特别是在胆碱能BF神经元系统的认知基础中发挥保护作用。研究结果还表明，雌激素可能至少部分通过内源性生长因子起作用。总的来说，这些数据表明，ERT可能是一个可行的治疗方法与DS加上痴呆症的妇女。(C)2002年爱思唯尔科技有限公司All rights reserved.
Estrogen maintains normal function of basal forebrain (BF) cholinergic neurons and estrogen replacement therapy (ERT) has therefore been proposed as a therapy for Alzheimer's disease (AD). We provide evidence to support this hypothesis in an animal model of Down syndrome (DS), a chromosome 16 segmental trisomy (Ts65Dn) mouse. These mice develop cholinergic degeneration similar to young adults with DS and AD patients. ERT has not been tested in women with DS, even though they are more likely than normosomic women to develop early menopause and AD. Female Ts65Dn and normosomic mice (11-15 months) received a subcutaneous estrogen pellet or a sham operation. After 60 days, estrogen treatment improved learning of a T-maze task and normalized behavior in the Ts65Dn mice in reversal learning of the task, a measure of cognitive flexibility. Stereological evaluation of choline acetyltransferase (ChAT) immunopositive BF neurons showed that estrogen increased cell size and total number of cholinergic neurons in the medial septum of Ts65Dn mice. In addition, estrogen increased NGF protein levels in the BF of trisomic mice. These findings support the emerging hypothesis that estrogen may play a protective role during neurodegeneration and cognitive decline, particularly in cholinergic BF neuronal systems underlying cognition. The findings also indicate that estrogen may act, at least partially, via endogenous growth factors. Collectively, the data suggest that ERT may be a viable therapeutic approach for women with DS coupled with dementia. (C) 2002 Elsevier Science Inc. All rights reserved.