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

被引：70

作者：

Tanaka, Hikari ^{[1
,2
]}

Homma, Hidenori ^{[1
,2
]}

Fujita, Kyota ^{[1
,2
]}

Kondo, Kanoh ^{[1
,2
]}

Yamada, Shingo ^{[3
]}

Jin, Xiaocen ^{[1
,2
]}

Waragai, Masaaki ^{[4
]}

Ohtomo, Gaku ^{[5
]}

Iwata, Atsushi ^{[5
]}

Tagawa, Kazuhiko ^{[1
,2
]}

Atsuta, Naoki ^{[6
]}

Katsuno, Masahisa ^{[6
]}

Tomita, Naoki

Furukawa, Katsutoshi

Saito, Yuko ^{[7
,8
]}

Saito, Takashi ^{[9
]}

Ichise, Ayaka ^{[10
]}

Shibata, Shinsuke ^{[10
]}

Arai, Hiroyuki ^{[7
]}

Saido, Takaomi ^{[9
]}

Sudol, Marius ^{[11
]}

Muramatsu, Shin-ichi ^{[12
]}

Okano, Hideyuki ^{[10
]}

Mufson, Elliott J. ^{[13
]}

Sobue, Gen ^{[6
]}

Murayama, Shigeo ^{[14
]}

Okazawa, Hitoshi ^{[1
,2
]}

机构：

[1] Tokyo Med & Dent Univ, Med Res Inst, Dept Neuropathol, Bunkyo Ku, 1-5-45 Yushima, Tokyo 1138510, Japan

[2] Tokyo Med & Dent Univ, Ctr Brain Integrat Res, Bunkyo Ku, 1-5-45 Yushima, Tokyo 1138510, Japan

[3] Shino Test Corp, Minami Ku, 2-29-14 Ohino Dai, Sagamihara, Kanagawa 2520331, Japan

[4] Higashi Matsudo Municipal Hosp, Dept Neurol, Matsudo, Chiba 2702222, Japan

[5] Univ Tokyo, Grad Sch Med, Dept Neurol, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan

[6] Nagoya Univ Grad Sch Med, Dept Neurol, Brain & Mind Res Ctr, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan

[7] Tohoku Univ, Inst Dev Aging & Canc, Div Brain Sci, Dept Geriatr & Gerontol,Aoba Ku, 4-1 Seiryo Cho, Sendai, Miyagi 9808575, Japan

[8] Natl Ctr Neurol & Psychiat, Natl Ctr Hosp, Dept Lab Med, 4-1-1 Ogawa Higahsi Machi, Kodaira, Tokyo, Japan

[9] RIKEN, Ctr Brain Sci, Lab Proteolyt Neurosci, 2-1 Hirosawa, Wako, Saitama 3510198, Japan

[10] Keio Univ, Sch Med, Dept Physiol, Shinjuku Ku, 35 Shinano Machi, Tokyo 1608582, Japan

[11] Natl Univ Singapore, Yong Loo Li Sch Med, Dept Physiol, 2 Med Dr, Singapore 117597, Singapore

[12] Jichi Med Univ, Dept Neurol, 3311-1 Yakushiji, Shimotsuke, Tochigi 3290496, Japan

[13] Barrow Neurol Inst, Dept Neurobiol & Neurol, 350 W Thomas Rd, Phoenix, AZ 85013 USA

[14] Tokyo Metropolitan Inst Gerontol, Dept Neuropathol Brain Bank Aging Res, Itabashi Ku, 35-2 Sakae Cho, Tokyo 1730015, Japan

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

关键词：

YES-ASSOCIATED PROTEIN; BALLOONED NEURONS; CELL-DEATH; NEURODEGENERATIVE DISEASES; CORTICOBASAL DEGENERATION; AMYLOID-BETA; ACTIVATION; PHOSPHORYLATION; APOPTOSIS; PATHWAY;

D O I：

10.1038/s41467-020-14353-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 (A beta) aggregates, supporting the feature of YAP-dependent necrosis. Suppression of early-stage neuronal death by AAV-YAPdeltaC reduces the later-stage extracellular A beta burden and cognitive impairment, suggesting that preclinical/prodromal YAP-dependent neuronal necrosis represents a target for AD therapeutics.

引用

页数：22

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