Year-end Sale % OFF 
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.
Highlights
The timing and characteristics of neuronal death in Alzheimer’s disease (AD) remain largely unknown
mild cognitive impairment (MCI) and AD were diagnosed by ICD-10, and the patients were categorized as having amnestic MCI
There was no significant difference in age between the different patient groups, but the proportion of female patients was slightly higher in the AD group than in the other groups
Summary
The timing and characteristics of neuronal death in Alzheimer’s disease (AD) remain largely unknown. We performed a comprehensive phosphoproteome analysis of four strains of AD model mice and human postmortem AD brains, and discovered three proteins whose phosphorylation state is altered at a very early stage before extracellular amyloid aggregates[20] One such protein is MARCKS, which anchors the actin cytoskeleton to the plasma membrane and plays a critical role in stabilizing the post-synaptic structure of dendritic spines[21]. We showed that the observed necrosis was caused by a deficiency of YAP, resulting in suppression of the transcriptional activity of TEAD, the final effector molecule of the Hippo pathway[11,12,13], in mouse AD models, human AD iPS neuron models and human postmortem MCI brains These findings unravel the occurrence of cell death at the early stage in AD, which could be a therapeutic target that prevents progression of AD
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
