Journal Article

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

Mufson, Elliott J., Homma, Hidenori, Katsuno, Masahisa, Atsuta, Naoki, Muramatsu, Shin-ichi, Jin, Xiaocen, Kondo, Kanoh, Arai, Hiroyuki, Ichise, Ayaka, Sudol, Marius, Yamada, Shingo, Okazawa, Hitoshi, Okano, Hideyuki, Tanaka, Hikari, Waragai, Masaaki, Saito, Yuko, Shibata, Shinsuke, Saito, Takashi, Furukawa, Katsutoshi, Saido, Takaomi, Tagawa, Kazuhiko, Iwata, Atsushi, Murayama, Shigeo, Fujita, Kyota, Ohtomo, Gaku, Sobue, Gen, Tomita, Naoki

2020

Overview

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. The precise mechanisms of neuronal cell death in neurodegeneration are not fully understood. Here the authors show that YAP-mediated neuronal necrosis is increased in pre-symptomatic stages of Alzheimer’s disease and intervention to the necrosis rescues extracellular Aβ aggregation and symptoms in a mouse model.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/106 / 13/109 / 13/2 / 13/44 / 13/95 / 14 / 14/1 / 14/19 / 14/28 / 14/34 / 14/63 / 14/69 / 42 / 42/109 / 42/41 / 631/378/1689/1283 / 631/378/1689/132/1283 / 631/80/82 / 64 / 64/110 / 64/60 / Adaptor Proteins, Signal Transducing - metabolism / Alanine / Alzheimer Disease - cerebrospinal fluid / Alzheimer Disease - metabolism / Alzheimer Disease - pathology / Alzheimer's disease / Amyloid beta-Peptides - metabolism / Animal models / Animals / Autopsy / Cell Cycle Proteins - metabolism / Cell death / Cell Nucleus - metabolism / Cognitive ability / Cognitive Dysfunction - cerebrospinal fluid / Cognitive Dysfunction - pathology / Computer Simulation / Disease Models, Animal / Endoplasmic reticulum / Endoplasmic Reticulum - pathology / Endoplasmic Reticulum - ultrastructure / Female / Genomes / HMGB1 Protein - cerebrospinal fluid / Humanities and Social Sciences / Humans / Impairment / Induced Pluripotent Stem Cells - metabolism / Kinases / Lysophospholipids - metabolism / Male / MARCKS protein / Mice, Transgenic / Mild cognitive impairment / Mortality / multidisciplinary / Necrosis / Neurodegeneration / Neurodegenerative diseases / Neurons / Neurons - metabolism / Neurons - pathology / Pathology / Science / Science (multidisciplinary) / Signal Transduction / Signs and symptoms / Sphingosine - analogs & derivatives / Sphingosine - metabolism / Substrates / Time-Lapse Imaging / Transcription Factors - metabolism / Yes-associated protein