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

Nature communications (2020-01-26)
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, Hitoshi Okazawa
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.

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