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YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology.
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-24 , DOI: 10.1038/s41467-020-14353-6 Hikari Tanaka 1 , Hidenori Homma 1 , Kyota Fujita 1 , Kanoh Kondo 1 , Shingo Yamada 2 , Xiaocen Jin 1 , Masaaki Waragai 3 , Gaku Ohtomo 4 , Atsushi Iwata 4 , Kazuhiko Tagawa 1 , Naoki Atsuta 5 , Masahisa Katsuno 5 , Naoki Tomita 6 , Katsutoshi Furukawa 6 , Yuko Saito 7 , Takashi Saito 8 , Ayaka Ichise 9 , Shinsuke Shibata 9 , Hiroyuki Arai 6 , Takaomi Saido 8 , Marius Sudol 10 , Shin-Ichi Muramatsu 11 , Hideyuki Okano 9 , Elliott J Mufson 12 , Gen Sobue 5 , Shigeo Murayama 13 , Hitoshi Okazawa 1
Nature Communications ( IF 14.7 ) Pub Date : 2020-01-24 , DOI: 10.1038/s41467-020-14353-6 Hikari Tanaka 1 , Hidenori Homma 1 , Kyota Fujita 1 , Kanoh Kondo 1 , Shingo Yamada 2 , Xiaocen Jin 1 , Masaaki Waragai 3 , Gaku Ohtomo 4 , Atsushi Iwata 4 , Kazuhiko Tagawa 1 , Naoki Atsuta 5 , Masahisa Katsuno 5 , Naoki Tomita 6 , Katsutoshi Furukawa 6 , Yuko Saito 7 , Takashi Saito 8 , Ayaka Ichise 9 , Shinsuke Shibata 9 , Hiroyuki Arai 6 , Takaomi Saido 8 , Marius Sudol 10 , Shin-Ichi Muramatsu 11 , Hideyuki Okano 9 , Elliott J Mufson 12 , Gen Sobue 5 , Shigeo Murayama 13 , Hitoshi Okazawa 1
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The timing and characteristics of neuronal death in Alzheimer's disease (AD) remain largely unknown. Here we examine AD mouse models with an original marker, myristoylated alanine-rich C-kinase substrate phosphorylated at serine 46 (pSer46-MARCKS), and reveal an increase of neuronal necrosis during pre-symptomatic phase and a subsequent decrease during symptomatic phase. Postmortem brains of mild cognitive impairment (MCI) rather than symptomatic AD patients reveal a remarkable increase of necrosis. In vivo imaging reveals instability of endoplasmic reticulum (ER) in mouse AD models and genome-edited human AD iPS cell-derived neurons. The level of nuclear Yes-associated protein (YAP) is remarkably decreased in such neurons under AD pathology due to the sequestration into cytoplasmic amyloid beta (Aβ) aggregates, supporting the feature of YAP-dependent necrosis. Suppression of early-stage neuronal death by AAV-YAPdeltaC reduces the later-stage extracellular Aβ burden and cognitive impairment, suggesting that preclinical/prodromal YAP-dependent neuronal necrosis represents a target for AD therapeutics.
中文翻译：
YAP依赖的坏死发生在阿尔茨海默氏病的早期阶段，并调节小鼠模型的病理。
阿尔茨海默氏病（AD）中神经元死亡的时间和特征仍然未知。在这里，我们检查了具有原始标记的AD小鼠模型，即在丝氨酸46（pSer46-MARCKS）处磷酸化的富含肉豆蔻酰的富含丙氨酸的C激酶底物（pSer46-MARCKS），并揭示了症状前期神经元坏死增加，而症状期后神经元坏死减少。轻度认知障碍（MCI）而非有症状的AD患者的死后大脑显示坏死显着增加。体内成像揭示了小鼠AD模型和基因组编辑的人AD iPS细胞来源的神经元中内质网（ER）的不稳定性。由于被隔离成细胞质淀粉样β（Aβ）聚集体，AD病理学下此类神经元中的核Yes-associated蛋白（YAP）水平明显降低，支持YAP依赖性坏死的特征。通过AAV-YAPdeltaC抑制早期神经元死亡可减少后期细胞外Aβ负担和认知障碍，这表明临床前/前驱性YAP依赖性神经元坏死代表了AD治疗的目标。
更新日期：2020-01-24
中文翻译：
YAP依赖的坏死发生在阿尔茨海默氏病的早期阶段，并调节小鼠模型的病理。
阿尔茨海默氏病（AD）中神经元死亡的时间和特征仍然未知。在这里，我们检查了具有原始标记的AD小鼠模型，即在丝氨酸46（pSer46-MARCKS）处磷酸化的富含肉豆蔻酰的富含丙氨酸的C激酶底物（pSer46-MARCKS），并揭示了症状前期神经元坏死增加，而症状期后神经元坏死减少。轻度认知障碍（MCI）而非有症状的AD患者的死后大脑显示坏死显着增加。体内成像揭示了小鼠AD模型和基因组编辑的人AD iPS细胞来源的神经元中内质网（ER）的不稳定性。由于被隔离成细胞质淀粉样β（Aβ）聚集体，AD病理学下此类神经元中的核Yes-associated蛋白（YAP）水平明显降低，支持YAP依赖性坏死的特征。通过AAV-YAPdeltaC抑制早期神经元死亡可减少后期细胞外Aβ负担和认知障碍，这表明临床前/前驱性YAP依赖性神经元坏死代表了AD治疗的目标。
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