YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology
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Published:2020-01-24
Issue:1
Volume:11
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Tanaka Hikari, Homma Hidenori, Fujita Kyota, Kondo Kanoh, Yamada Shingo, Jin Xiaocen, Waragai MasaakiORCID, Ohtomo Gaku, Iwata Atsushi, Tagawa Kazuhiko, Atsuta Naoki, Katsuno MasahisaORCID, Tomita Naoki, Furukawa Katsutoshi, Saito Yuko, Saito Takashi, Ichise Ayaka, Shibata ShinsukeORCID, Arai Hiroyuki, Saido Takaomi, Sudol Marius, Muramatsu Shin-ichiORCID, Okano Hideyuki, Mufson Elliott J., Sobue GenORCID, Murayama Shigeo, Okazawa Hitoshi
Abstract
AbstractThe 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.
Funder
Japan Agency for Medical Research and Development Ministry of Education, Culture, Sports, Science and Technology
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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