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Title: YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology
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.
Issue Date: 24-Jan-2020
Publisher: Nature Research
Citation: 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. (2020-01-24). YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology. Nature Communications 11 (1) : 507. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
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. © 2020, The Author(s).
Source Title: Nature Communications
ISSN: 20411723
DOI: 10.1038/s41467-020-14353-6
Rights: Attribution 4.0 International
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