Yang Seung-Hoon, Lee Dongkeun Kenneth, Shin Jisu, Lee Sejin, Baek Seungyeop, Kim Jiyoon, Jung Hoyong, Hah Jung-Mi, Kim YoungSoo
Convergence Research Center for Dementia and Center for Neuro-Medicine, Brain Science Institute Korea Institute of Science and Technology, Seoul, Korea.
Biological Chemistry Program, Korea University of Science and Technology, Daejeon, Korea.
EMBO Mol Med. 2017 Jan;9(1):61-77. doi: 10.15252/emmm.201606566.
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive symptoms of learning and memory deficits. Such cognitive impairments are attributed to brain atrophy resulting from progressive neuronal and synaptic loss; therefore, alleviation of neural cell death is as an important target of treatment as other classical hallmarks of AD, such as aggregation of amyloid-β (Aβ) and hyperphosphorylation of tau. Here, we found that an anti-necroptotic molecule necrostatin-1 (Nec-1) directly targets Aβ and tau proteins, alleviates brain cell death and ameliorates cognitive impairment in AD models. In the cortex and hippocampus of APP/PS1 double-transgenic mice, Nec-1 treatment reduced the levels of Aβ oligomers, plaques and hyperphosphorylated tau without affecting production of Aβ, while it altered the levels of apoptotic marker proteins. Our results showing multiple beneficial modes of action of Nec-1 against AD provide evidence that Nec-1 may serve an important role in the development of preventive approach for AD.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征为学习和记忆缺陷的认知症状。此类认知障碍归因于神经元和突触渐进性丧失导致的脑萎缩；因此，减轻神经细胞死亡与AD的其他经典特征（如β淀粉样蛋白（Aβ）聚集和tau蛋白过度磷酸化）一样，是重要的治疗靶点。在此，我们发现一种抗坏死性凋亡分子坏死素-1（Nec-1）直接作用于Aβ和tau蛋白，减轻AD模型中的脑细胞死亡并改善认知障碍。在APP/PS1双转基因小鼠的皮质和海马中，Nec-1治疗降低了Aβ寡聚体、斑块和过度磷酸化tau的水平，而不影响Aβ的产生，同时改变了凋亡标记蛋白的水平。我们的结果表明Nec-1对AD具有多种有益作用模式，这为Nec-1可能在AD预防方法的开发中发挥重要作用提供了证据。
