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 - 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.
UR - https://www.scopus.com/pages/publications/85078173772
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 -