YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology
Open accessAbstract
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.
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Significant neuronal necrosis occurs at very early stages of presymptomatic Alzheimer's disease; HMGB1 levels are significantly elevated in clinically diagnosed presymptomatic Alzheimer's disease but not in symptomatic advanced-stage Alzheimer's disease.
“significant neuronal necrosis occurs at very early stages of presymptomatic AD; hence, HMGB1 levels are significantly elevated in clinically diagnosed presymptomatic AD but not in symptomatic advanced‐stage AD. 91”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [91]
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References 64 · Cited by 119
- Authors
- 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, S.-I., Okano, H., Mufson, E. J., Sobue, G., Murayama, S., & Okazawa, H.
- Affiliations
- Tokyo Medical and Dental University (JP)
- Shino-Test Corporation (JP)
- Matsudo City Hospital (JP)
- The University of Tokyo (JP)
- Brain & Mind Research Center, Nagoya University (JP)
- Tohoku University (JP)
- National Center Hospital of Neurology and Psychiatry (JP)
- RIKEN Center for Brain Science (JP)
- Keio University (JP)
- National University of Singapore (SG)
- Jichi Medical University (JP)
- Barrow Neurological Institute (US)
- Tokyo Metropolitan Institute of Gerontology (JP)
- Corresponding author
- Okazawa, Hitoshi
- ORCID
- Tanaka, Hikari
- Homma, Hidenori
- Fujita, Kyota
- Kondo, Kanoh
- Yamada, Shingo
- Jin, Xiaocen
- Waragai, Masaaki
- Ohtomo, Gaku
- Iwata, Atsushi
- Atsuta, Naoki
- Katsuno, Masahisa
- Tomita, Naoki
- Furukawa, Katsutoshi
- Saito, Yuko
- Saito, Takashi
- Shibata, Shinsuke
- Arai, Hiroyuki
- Saido, Takaomi
- Sudol, Marius
- Muramatsu, Shin-ichi
- Okano, Hideyuki
- Mufson, Elliott J.
- Sobue, Gen
- Murayama, Shigeo
- Okazawa, Hitoshi
- Venue
- Nature Communications
- Published
- 2020-01-24
- Volume
- 11
- Issue
- 1
- Pages
- 507-507
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6981281
- OpenAlex
- W3002971422
- Cited by
- 119
- References
- 64
- Citations by year
- 2026: 12 · 2025: 23 · 2024: 26 · 2023: 16 · 2022: 22 · 2021: 16 · 2020: 4
- FWCI
- 8.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Japan Agency for Medical Research and Development (JP18dm0207013h0005, JP18dm0107057h0002)
- Ministry of Education, Culture, Sports, Science and Technology (22110001, 22110002)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, neuronal necrosis, YAP, amyloid-beta, mild cognitive impairment, preclinical Alzheimer's disease, MARCKS phosphorylation, AAV gene therapy, iPSC-derived neurons, cognitive impairment, amyloid burden
- MeSH terms
- YAP-Signaling Proteins, Alzheimer Disease, Animals, Cell Nucleus, Computer Simulation, Disease Models, Animal, Endoplasmic Reticulum, Female, Humans, Lysophospholipids, Male, Mice, Transgenic, Necrosis, Neurons, Sphingosine, Transcription Factors, Signal Transduction, Amyloid beta-Peptides, Cell Cycle Proteins, HMGB1 Protein, Adaptor Proteins, Signal Transducing, Induced Pluripotent Stem Cells, Time-Lapse Imaging, Cognitive Dysfunction
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