YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology

Hikari Tanaka, Hidenori Homma, Kyota Fujita, Kanoh Kondo, Shingo Yamada, Xiaocen Jin, Masaaki Waragai, Gaku Ohtomo, Atsushi Iwata, Kazuhiko Tagawa, Naoki Atsuta, Masahisa Katsuno, Naoki Tomita, Katsutoshi Furukawa, Yuko Saito, Takashi Saito, Ayaka Ichise, Shinsuke Shibata, Hiroyuki Arai, Takaomi Saido, Marius Sudol, Shin-ichi Muramatsu, Hideyuki Okano, Elliott J. Mufson, Gen Sobue, Shigeo Murayama and Hitoshi Okazawa ()
Additional contact information
Hikari Tanaka: Tokyo Medical and Dental University
Hidenori Homma: Tokyo Medical and Dental University
Kyota Fujita: Tokyo Medical and Dental University
Kanoh Kondo: Tokyo Medical and Dental University
Shingo Yamada: Shino-Test Corporation, 2-29-14, Ohino-dai, Minami-ku
Xiaocen Jin: Tokyo Medical and Dental University
Masaaki Waragai: Higashi Matsudo Municipal Hospital
Gaku Ohtomo: The University of Tokyo, Graduate School of Medicine
Atsushi Iwata: The University of Tokyo, Graduate School of Medicine
Kazuhiko Tagawa: Tokyo Medical and Dental University
Naoki Atsuta: Brain and Mind Research Center, Nagoya University Graduate School of Medicine
Masahisa Katsuno: Brain and Mind Research Center, Nagoya University Graduate School of Medicine
Naoki Tomita: Tohoku University
Katsutoshi Furukawa: Tohoku University
Yuko Saito: National Center of Neurology and Psychiatry
Takashi Saito: RIKEN Center for Brain Science
Ayaka Ichise: Keio University School of Medicine
Shinsuke Shibata: Keio University School of Medicine
Hiroyuki Arai: Tohoku University
Takaomi Saido: RIKEN Center for Brain Science
Marius Sudol: National University of Singapore, Yong Loo Li School of Medicine
Shin-ichi Muramatsu: Jichi Medical University
Hideyuki Okano: Keio University School of Medicine
Elliott J. Mufson: Barrow Neurological Institute
Gen Sobue: Brain and Mind Research Center, Nagoya University Graduate School of Medicine
Shigeo Murayama: Brain Bank for Aging Research, Tokyo Metropolitan Institute of Gerontology
Hitoshi Okazawa: Tokyo Medical and Dental University

Nature Communications, 2020, vol. 11, issue 1, 1-22

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14353-6

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