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

Nat Commun. 2020 Jan 24;11(1):507. doi: 10.1038/s41467-020-14353-6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*

Substances

  • Adaptor Proteins, Signal Transducing
  • Amyloid beta-Peptides
  • Cell Cycle Proteins
  • HMGB1 Protein
  • Lysophospholipids
  • Transcription Factors
  • YAP1 protein, human
  • Yap1 protein, mouse
  • sphingosine 1-phosphate
  • Sphingosine