1. YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology
- Author
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Gaku Ohtomo, Kanoh Kondo, Katsutoshi Furukawa, Masaaki Waragai, Hidenori Homma, Shinsuke Shibata, Marius Sudol, Shingo Yamada, Hiroyuki Arai, Yuko Saito, Atsushi Iwata, Naoki Atsuta, Xiaocen Jin, Kazuhiko Tagawa, Hikari Tanaka, Ayaka Ichise, Takashi Saito, Masahisa Katsuno, Naoki Tomita, Hideyuki Okano, Kyota Fujita, Shin-ichi Muramatsu, Elliott J. Mufson, Gen Sobue, Hitoshi Okazawa, Shigeo Murayama, and Takaomi C. Saido
- Subjects
0301 basic medicine ,Male ,Pathology ,Necrosis ,General Physics and Astronomy ,Cell Cycle Proteins ,Endoplasmic Reticulum ,0302 clinical medicine ,Sphingosine ,HMGB1 Protein ,lcsh:Science ,Neurons ,Multidisciplinary ,biology ,Alzheimer's disease ,medicine.anatomical_structure ,Phosphorylation ,Female ,medicine.symptom ,Signal transduction ,Signal Transduction ,Cell death ,medicine.medical_specialty ,Amyloid beta ,Science ,Induced Pluripotent Stem Cells ,Mice, Transgenic ,Time-Lapse Imaging ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Alzheimer Disease ,medicine ,Extracellular ,Animals ,Humans ,Cognitive Dysfunction ,Computer Simulation ,Adaptor Proteins, Signal Transducing ,Cell Nucleus ,Amyloid beta-Peptides ,business.industry ,Endoplasmic reticulum ,YAP-Signaling Proteins ,General Chemistry ,medicine.disease ,Cell nucleus ,Disease Models, Animal ,030104 developmental biology ,biology.protein ,lcsh:Q ,Lysophospholipids ,business ,030217 neurology & neurosurgery ,Transcription Factors - Abstract
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., The precise mechanisms of neuronal cell death in neurodegeneration are not fully understood. Here the authors show that YAP-mediated neuronal necrosis is increased in pre-symptomatic stages of Alzheimer’s disease and intervention to the necrosis rescues extracellular Aβ aggregation and symptoms in a mouse model.
- Published
- 2020