TY - JOUR
T1 - YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology
AU - Tanaka, Hikari
AU - Homma, Hidenori
AU - Fujita, Kyota
AU - Kondo, Kanoh
AU - Yamada, Shingo
AU - Jin, Xiaocen
AU - Waragai, Masaaki
AU - Ohtomo, Gaku
AU - Iwata, Atsushi
AU - Tagawa, Kazuhiko
AU - Atsuta, Naoki
AU - Katsuno, Masahisa
AU - Tomita, Naoki
AU - Furukawa, Katsutoshi
AU - Saito, Yuko
AU - Saito, Takashi
AU - Ichise, Ayaka
AU - Shibata, Shinsuke
AU - Arai, Hiroyuki
AU - Saido, Takaomi
AU - Sudol, Marius
AU - Muramatsu, Shin ichi
AU - Okano, Hideyuki
AU - Mufson, Elliott J.
AU - Sobue, Gen
AU - Murayama, Shigeo
AU - Okazawa, Hitoshi
N1 - Funding Information:
This work was supported by Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from the Japan Agency for Medical Research and Development (AMED) (JP18dm0207013h0005); the Strategic Research Program for Brain Sciences (SRPBS) (JP18dm0107057h0002); and a Grant-in-Aid for Scientific Research on Innovative Areas “Foundation of Synapse and Neurocircuit Pathology” (22110001, 22110002) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to H.O. This work is also partially supported by Strategic Research Program for Brain Sciences (SRPBS) (JP17dm0107057h0002) to K.T., brain bank supported by AMED (JP18dm0107103) to Y.S., and NIH grant (PO1AG14449) to E.M. We thank Marie Tanaka, Tayoko Tajima, and Emiko Yamanishi (Neuropathology, TMDU), and Naomi Takino and Mika Ito (Jichi Medical University), for technical support. We also thank Prof. Yutaka Hata, (Medical Biochemistry, TMDU) for pLL3.7-ires-GFP-TEAD-responsive-H2B-mCherry and RIKEN BioResource Center for providing APP-KI mice.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-14353-6
DO - 10.1038/s41467-020-14353-6
M3 - Article
C2 - 31980612
AN - SCOPUS:85078173772
SN - 2041-1723
VL - 11
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 507
ER -
