Title

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.

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

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