YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology.
Department
Neurobiology
Document Type
Article
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.
Keywords
Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amyloid beta-Peptides, Animals, Cell Cycle Proteins, Cell Nucleus, Cognitive Dysfunction, Computer Simulation, Disease Models, Animal, Endoplasmic Reticulum, Female, HMGB1 Protein, Humans, Induced Pluripotent Stem Cells, Lysophospholipids, Male, Mice, Transgenic, Necrosis, Neurons, Signal Transduction, Sphingosine, Time-Lapse Imaging, Transcription Factors
Medical Subject Headings
Adaptor Proteins, Signal Transducing; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Cycle Proteins; Cell Nucleus; Cognitive Dysfunction; Computer Simulation; Disease Models, Animal; Endoplasmic Reticulum; Female; HMGB1 Protein; Humans; Induced Pluripotent Stem Cells; Lysophospholipids; Male; Mice, Transgenic; Necrosis; Neurons; Signal Transduction; Sphingosine; Time-Lapse Imaging; Transcription Factors
Publication Date
1-24-2020
Publication Title
Nat Commun
ISSN
2041-1723
Volume
11
Issue
1
First Page
507
Last Page
507
PubMed ID
31980612
Digital Object Identifier (DOI)
10.1038/s41467-020-14353-6
Recommended Citation
Tanaka, Hikari; Homma, Hidenori; Fujita, Kyota; Kondo, Kanoh; Yamada, Shingo; Jin, Xiaocen; Waragai, Masaaki; Ohtomo, Gaku; Iwata, Atsushi; Tagawa, Kazuhiko; Atsuta, Naoki; Katsuno, Masahisa; Tomita, Naoki; Furukawa, Katsutoshi; Saito, Yuko; Saito, Takashi; Ichise, Ayaka; Shibata, Shinsuke; Arai, Hiroyuki; Saido, Takaomi; Sudol, Marius; Muramatsu, Shin-Ichi; Okano, Hideyuki; Mufson, Elliott J.; Sobue, Gen; Murayama, Shigeo; and Okazawa, Hitoshi, "YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology." (2020). Translational Neuroscience. 491.
https://scholar.barrowneuro.org/neurobiology/491