Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model
Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model
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DOI：
10.1016/j.brainres.2008.03.079
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发表时间：
2008-06-24
期刊：
影响因子：
2.9
通讯作者：
Matsuoka, Yasuji
中科院分区：
文献类型：
--
作者：
Hirata-Fukae, Chiho;Li, Hui-Fang;Matsuoka, Yasuji
流行病学研究表明，即使在调整年龄后，女性患阿尔茨海默病（AD）的风险也更高。虽然转基因AD小鼠模型会出现AD相关的β淀粉样蛋白（Abeta）和/或tau病理，但性别差异在这些模型中尚未得到很好的证明。在本研究中，我们发现表达突变的APP、早老素-1和tau的雌性3xTg-AD转基因小鼠具有明显更强的Abeta病理。我们还发现，与雄性小鼠相比，雌性小鼠的β -分泌酶活性有所增加，而neprilysin则有所减少；这表明，增加的β生成和减少的β降解的结合可能导致女性患AD的风险增加。在3xTg-AD小鼠中，性别不影响磷酸化tau蛋白的水平，而在雌性小鼠中则明显更具攻击性。这些结果表明，β途径与女性患阿尔茨海默病的高风险有关。除了在9、16和23月龄时比较性别间的病理外，我们还在其他年龄点检查了Abeta病理的进展；即在雄性3xTg-AD小鼠3、6、9、12、16、20和23月龄时的脑β负荷、神经元内低聚β分布和斑块负荷。这些发现证实了3xTg-AD转基因小鼠的进行性Abeta病理，并为其在治疗性研究中的应用提供了指导。(C) 2008 Elsevier B.V.版权所有
Epidemiological studies indicate that women have a higher risk of Alzheimer's disease (AD) even after adjustment for age. Though transgenic mouse models of AD develop AD-related amyloid beta (Abeta) and/or tau pathology, gender differences have not been well documented in these models. In this study, we found that female 3xTg-AD transgenic mice expressing mutant APP, presenilin-1 and tau have significantly more aggressive Abeta pathology. We also found an increase in beta-secretase activity and a reduction of neprilysin in female mice compared to males; this suggests that a combination of increased Abeta production and decreased Abeta degradation may contribute to higher risk of AD in females. In contrast to significantly more aggressive Abeta pathology in females, gender did not affect the levels of phosphorylated tau in 3xTg-AD mice. These results point to the involvement of Abeta pathways in the higher risk of AD in women. In addition to comparison of pathology between genders at 9, 16 and 23 months of age, we examined the progression of Abeta pathology at additional age points; i.e., brain Abeta load, intraneuronal oligomeric Abeta distribution and plaque load, in male 3xTg-AD mice at 3,6,9,12,16,20 and 23 months of age. These findings confirm progressive Abeta pathology in 3xTg-AD transgenic mice, and provide guidance for their use in therapeutic research. (C) 2008 Elsevier B.V. All rights reserved.