RRC ID 58391
Author Tanaka H, Homma H, Fujita K, Kondo K, Yamada S, Jin X, Waragai M, Ohtomo G, Iwata A, Tagawa K, Atsuta N, Katsuno M, Tomita N, Furukawa K, Saito Y, Saito T, Ichise A, Shibata S, Arai H, Saido T, Sudol M, Muramatsu SI, Okano H, Mufson EJ, Sobue G, Murayama S, Okazawa H.
Title YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology.
Journal Nat Commun
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.
Volume 11(1)
Pages 507
Published 2020-1-24
DOI 10.1038/s41467-020-14353-6
PII 10.1038/s41467-020-14353-6
PMID 31980612
PMC PMC6981281
MeSH Adaptor Proteins, Signal Transducing / metabolism* Alzheimer Disease / cerebrospinal fluid Alzheimer Disease / metabolism* Alzheimer Disease / pathology* Amyloid beta-Peptides / metabolism Animals Cell Cycle Proteins / metabolism* Cell Nucleus / metabolism Cognitive Dysfunction / cerebrospinal fluid Cognitive Dysfunction / pathology Computer Simulation Disease Models, Animal Endoplasmic Reticulum / pathology Endoplasmic Reticulum / ultrastructure Female HMGB1 Protein / cerebrospinal fluid Humans Induced Pluripotent Stem Cells / metabolism Lysophospholipids / metabolism Male Mice, Transgenic Necrosis Neurons / metabolism Neurons / pathology Signal Transduction Sphingosine / analogs & derivatives Sphingosine / metabolism Time-Lapse Imaging Transcription Factors / metabolism* YAP-Signaling Proteins
IF 12.121
Times Cited 1
Mice RBRC06334