High mobility group box protein‐1 inhibits microglial Aβ clearance and enhances Aβ neurotoxicity
High mobility group box protein‐1 inhibits microglial Aβ clearance and enhances Aβ neurotoxicity
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DOI：
10.1002/jnr.20340
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发表时间：
2004-12
影响因子：
4.2
通讯作者：
K. Takata;Y. Kitamura;D. Tsuchiya;T. Kawasaki;T. Taniguchi;S. Shimohama
中科院分区：
文献类型：
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作者：
K. Takata;Y. Kitamura;D. Tsuchiya;T. Kawasaki;T. Taniguchi;S. Shimohama
阿尔茨海默病(AD)的一个致病特征是形成细胞外老年斑和聚集的小胶质细胞。根据淀粉样蛋白假说，淀粉样蛋白-β(A-β)多肽在脑实质中的增加或积聚是影响AD病理的主要事件。虽然小胶质细胞在AD病理中的作用尚未阐明，但它们参与Aβ清除已被注意到。高迁移率族蛋白-1(HMGB1)是一种含量丰富的非组蛋白。我们最近报道HMGB1与老年斑相关，AD脑内总蛋白水平显著升高。在本研究中，在红藻氨酸和Aβ1-42(Aβ42)注射的大鼠海马区死亡神经元周围观察到弥漫性HMGB1免疫反应。在注射Aβ42的大鼠中，HMGB1也与Aβ共存，但在转基因小鼠中不存在，转基因小鼠显示出大量的Aβ产生，而它们的大脑中没有神经元丢失。此外，联合注射HMGB1可延缓Aβ42的清除，加速Aβ42所致大鼠的神经变性。这些结果提示，死亡神经元释放的HMGB1可能抑制小胶质细胞Aβ42的清除，从而增强Aβ42的神经毒性。因此，HMGB1可能是AD治疗策略研究的另一个靶点。©2004 Wiley-Liss Inc.
One pathogenic characteristic of Alzheimer's disease (AD) is the formation of extracellular senile plaques with accumulated microglia. According to the amyloid hypothesis, the increase or accumulation of amyloid‐β (Aβ) peptides in the brain parenchyma is the primary event that influences AD pathology. Although the role of microglia in AD pathology has not been clarified, their involvement in Aβ clearance has been noted. High mobility group box protein‐1 (HMGB1) is an abundant nonhistone chromosomal protein. We reported recently that HMGB1 was associated with senile plaques and the total protein level significantly increased in AD brain. In this study, diffuse HMGB1 immunoreactivity was observed around dying neurons in the kainic acid‐ and Aβ1–42 (Aβ42)‐injected rat hippocampi. HMGB1 also colocalized with Aβ in the Aβ42‐injected rats but not in transgenic mice, which show massive Aβ production without neuronal loss in their brains. Furthermore, coinjection of HMGB1 delayed the clearance of Aβ42 and accelerated neurodegeneration in Aβ42‐injected rats. These results suggest that HMGB1 released from dying neurons may inhibit microglial Aβ42 clearance and enhance the neurotoxicity of Aβ42. HMGB1 may thus be another target in the investigation of a therapeutic strategy for AD. © 2004 Wiley‐Liss, Inc.