Takata Kazuyuki, Kitamura Yoshihisa, Tsuchiya Daiju, Kawasaki Toshiyuki, Taniguchi Takashi, Shimohama Shun
Department of Neurobiology, Kyoto Pharmaceutical University, Kyoto, Japan.
J Neurosci Res. 2004 Dec 15;78(6):880-91. doi: 10.1002/jnr.20340.
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-beta (Abeta) 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 Abeta 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 Abeta1-42 (Abeta42)-injected rat hippocampi. HMGB1 also colocalized with Abeta in the Abeta42-injected rats but not in transgenic mice, which show massive Abeta production without neuronal loss in their brains. Furthermore, coinjection of HMGB1 delayed the clearance of Abeta42 and accelerated neurodegeneration in Abeta42-injected rats. These results suggest that HMGB1 released from dying neurons may inhibit microglial Abeta42 clearance and enhance the neurotoxicity of Abeta42. HMGB1 may thus be another target in the investigation of a therapeutic strategy for AD.
阿尔茨海默病（AD）的一个致病特征是细胞外老年斑的形成以及小胶质细胞的聚集。根据淀粉样蛋白假说，脑实质中β淀粉样蛋白（Aβ）肽的增加或积累是影响AD病理的主要事件。尽管小胶质细胞在AD病理中的作用尚未明确，但已注意到它们参与Aβ的清除。高迁移率族蛋白B1（HMGB1）是一种丰富的非组蛋白染色体蛋白。我们最近报道，HMGB1与老年斑有关，且在AD脑中总蛋白水平显著升高。在本研究中，在注射了 kainic 酸和 Aβ1-42（Aβ42）的大鼠海马体中，在濒死神经元周围观察到弥漫性的HMGB1免疫反应性。在注射了Aβ42的大鼠中，HMGB1也与Aβ共定位，但在转基因小鼠中并非如此，转基因小鼠脑内大量产生Aβ但无神经元损失。此外，共注射HMGB1延迟了Aβ42的清除，并加速了注射Aβ42大鼠的神经退行性变。这些结果表明，从濒死神经元释放的HMGB1可能抑制小胶质细胞对Aβ42的清除，并增强Aβ42的神经毒性。因此，HMGB1可能是AD治疗策略研究中的另一个靶点。
