HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer's disease.
HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer's disease.
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DOI：
10.1038/srep31895
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发表时间：
2016-08-25
影响因子：
4.6
通讯作者：
Okazawa H
中科院分区：
文献类型：
--
作者：
Fujita K;Motoki K;Tagawa K;Chen X;Hama H;Nakajima K;Homma H;Tamura T;Watanabe H;Katsuno M;Matsumi C;Kajikawa M;Saito T;Saido T;Sobue G;Miyawaki A;Okazawa H
阿尔茨海默病（AD）是最常见的神经退行性疾病，但它仍然是一个棘手的条件。其发病机制主要归因于两种分子Aβ和tau的聚集和传递;然而，其他病理机制也是可能的。在这里，我们揭示了MARCKS（一种调节肌动蛋白网络稳定性的膜下蛋白）的磷酸化发生在Aβ聚集之前的Ser 46处，并在人类和小鼠大脑中的整个AD过程中持续存在。此外，从坏死或过度兴奋的神经元释放的HMGB 1与TLR 4结合，通过MAP激酶触发MARCKS的特异性磷酸化，并诱导神经突变性，这是AD病理学的经典标志。皮下注射一种新开发的抗HMGB 1单克隆抗体，即使在存在Aβ斑块的情况下也能强烈抑制神经突变性，并在小鼠模型中完全恢复认知障碍。HMGB 1和Aβ相互影响另一分子的聚合，抗HMGB 1单克隆抗体的治疗作用是通过Aβ依赖和Aβ非依赖机制介导的。我们认为HMGB 1与Aβ和tau蛋白是共同促进AD病理学的重要致病分子，是临床前抗体治疗延缓AD发病的新的关键分子靶点。
Alzheimer’s disease (AD) is the most common neurodegenerative disease, but it remains an intractable condition. Its pathogenesis is predominantly attributed to the aggregation and transmission of two molecules, Aβ and tau; however, other pathological mechanisms are possible. Here, we reveal that phosphorylation of MARCKS, a submembrane protein that regulates the stability of the actin network, occurs at Ser46 prior to aggregation of Aβ and is sustained throughout the course of AD in human and mouse brains. Furthermore, HMGB1 released from necrotic or hyperexcitatory neurons binds to TLR4, triggers the specific phosphorylation of MARCKS via MAP kinases, and induces neurite degeneration, the classical hallmark of AD pathology. Subcutaneous injection of a newly developed monoclonal antibody against HMGB1 strongly inhibits neurite degeneration even in the presence of Aβ plaques and completely recovers cognitive impairment in a mouse model. HMGB1 and Aβ mutually affect polymerization of the other molecule, and the therapeutic effects of the anti-HMGB1 monoclonal antibody are mediated by Aβ-dependent and Aβ-independent mechanisms. We propose that HMGB1 is a critical pathogenic molecule promoting AD pathology in parallel with Aβ and tau and a new key molecular target of preclinical antibody therapy to delay the onset of AD.