Department of Neuropathology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Laboratory for Cell Function Dynamics, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
Sci Rep. 2016 Aug 25;6:31895. doi: 10.1038/srep31895.
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.
阿尔茨海默病（AD）是最常见的神经退行性疾病，但它仍然是一种难以治愈的疾病。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，也可能存在其他病理机制。在这里，我们揭示了 MARCKS 的磷酸化，MARCKS 是一种调节肌动蛋白网络稳定性的亚膜蛋白，在 Aβ聚集之前发生在 Ser46 上，并在人和小鼠大脑的 AD 病程中持续存在。此外，来自坏死或过度兴奋神经元的 HMGB1 与 TLR4 结合，通过 MAP 激酶触发 MARCKS 的特异性磷酸化，并诱导神经突退化，这是 AD 病理学的经典标志。针对 HMGB1 的新开发的单克隆抗体的皮下注射即使在存在 Aβ斑块的情况下也能强烈抑制神经突退化，并在小鼠模型中完全恢复认知障碍。HMGB1 和 Aβ相互影响另一种分子的聚合，针对 HMGB1 的单克隆抗体的治疗效果通过 Aβ 依赖和 Aβ 非依赖机制介导。我们提出 HMGB1 是一种关键的致病分子，与 Aβ 和 tau 平行促进 AD 病理学，是延迟 AD 发病的临床前抗体治疗的新关键分子靶标。
