APPswe/Aβ regulation of osteoclast activation and RAGE expression in an age-dependent manner.
APPswe/Aβ regulation of osteoclast activation and RAGE expression in an age-dependent manner.
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DOI：
10.1002/jbmr.299
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发表时间：
2011-05
影响因子：
6.2
通讯作者：
Xiong, Wen-Cheng
中科院分区：
文献类型：
--
作者：
Cui, Shun;Xiong, Fei;Hong, Yan;Jung, Ji-Ung;Li, Xing-Sheng;Liu, Jian-Zhong;Yan, Riqiang;Mei, Lin;Feng, Xu;Xiong, Wen-Cheng
阿尔茨海默病（AD）是最可怕的神经退行性疾病之一，其特征是皮层和脑血管Aβ （β淀粉样肽）沉积、神经原纤维缠结、慢性炎症和神经元丢失。阿尔茨海默病患者通常观察到骨折率增加和骨密度降低，这表明这两种疾病之间存在共同点。然而，很少有研究可以解决这个问题。在这里，我们提供了淀粉样蛋白前体蛋白（APP）和a β在体外和体内调节破骨细胞（OC）分化功能的证据。在朊病毒启动子控制下表达APP瑞典突变（APPswe）的Tg2576小鼠对OC的激活表现出双相效应，年轻小鼠（< 4月龄）OC升高，而老年Tg2576小鼠（bb0 4月龄）OC降低。年轻Tg2576小鼠OC的增加似乎是由Aβ低聚物和RAGE（晚期糖基化终产物受体）在BMMs中的表达介导的。然而，老年Tg2576小鼠OC形成和活性的减少可能是由于老年Tg2576小鼠中sRAGE的增加，sRAGE是RANKL诱导的破骨细胞生成的抑制剂。这些结果表明APPswe/ a β具有意想不到的功能，揭示了AD患者骨重塑改变的机制，并暗示APP/ a β和RAGE是AD和骨质疏松症的共同特征。
Alzheimer’s disease (AD), one of the most dreaded neurodegenerative disorders, is characterized by cortical and cerebrovascular Aβ (amyloid β peptide) deposits, neurofibrillary tangles, chronic inflammation, and neuronal loss. Increased bone fracture rates and reduced bone density are commonly observed in patients with AD, suggesting a common denominator(s) between both disorders. However, very few studies are available that have addressed this issue. Here, we present evidence for a function of amyloid precursor protein (APP) and Aβ in regulating osteoclast (OC) differentiation in vitro and in vivo. Tg2576 mice, which expresses Swedish mutation of APP (APPswe) under the control of prion promoter, exhibit biphasic effects on OC activation, with an increase of OC in younger mice (< 4 month old), but a decrease in older Tg2576 mice (> 4 month old). The increase of OC in young Tg2576 mice appears to be mediated by Aβ oligomers and RAGE (receptor for advanced glycation end products) expression in BMMs. However, the decrease of OC formation and activity in older Tg2576 mice may be due to the increase of sRAGE in aged Tg2576 mice, an inhibitor of RANKL induced osteoclastogenesis. These results suggest an unexpected function of APPswe/Aβ, reveal a mechanism underlying altered bone remodeling in AD patients, and implicate APP/Aβ and RAGE as common denominators for both AD and osteoporosis.
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