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Ibrutinib modulates Aβ/tau pathology, neuroinflammation, and cognitive function in mouse models of Alzheimer's disease

Title
Ibrutinib modulates Aβ/tau pathology, neuroinflammation, and cognitive function in mouse models of Alzheimer's disease
Authors
Lee, Hyun-juJeon, Seong GakKim, JieunKang, Ri JinKim, Seong-MinHan, Kyung-MinPark, HyunHeeKim, Ki-taekSung, You MeNam, Hye YeonKoh, Young HoSong, MinseokSuk, KyounghoHoe, Hyang-Sook
DGIST Authors
Lee, Hyun-ju; Jeon, Seong Gak; Kim, Jieun; Kang, Ri Jin; Kim, Seong-Min; Han, Kyung-Min; Park, HyunHee; Kim, Ki-taek; Sung, You Me; Nam, Hye Yeon; Koh, Young Ho; Song, Minseok; Suk, Kyoungho; Hoe, Hyang-Sook
Issue Date
2021-03
Citation
Aging Cell, 20(3), e13332
Type
Article
Author Keywords
5xFAD miceAlzheimer&aposs diseaseamyloid betaibrutinibneuroinflammationPS19 micespinogenesistau
ISSN
1474-9718
Abstract
We previously demonstrated that ibrutinib modulates LPS-induced neuroinflammation in vitro and in vivo, but its effects on the pathology of Alzheimer's disease (AD) and cognitive function have not been investigated. Here, we investigated the effects of ibrutinib in two mouse models of AD. In 5xFAD mice, ibrutinib injection significantly reduced Aβ plaque levels by promoting the non-amyloidogenic pathway of APP cleavage, decreased Aβ-induced neuroinflammatory responses, and significantly downregulated phosphorylation of tau by reducing levels of phosphorylated cyclin-dependent kinase-5 (p-CDK5). Importantly, tau-mediated neuroinflammation and tau phosphorylation were also alleviated by ibrutinib injection in PS19 mice. In 5xFAD mice, ibrutinib improved long-term memory and dendritic spine number, whereas in PS19 mice, ibrutinib did not alter short- and long-term memory but promoted dendritic spinogenesis. Interestingly, the induction of dendritic spinogenesis by ibrutinib was dependent on the phosphorylation of phosphoinositide 3-kinase (PI3K). Overall, our results suggest that ibrutinib modulates AD-associated pathology and cognitive function and may be a potential therapy for AD. © 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
URI
http://hdl.handle.net/20.500.11750/13976
DOI
10.1111/acel.13332
Publisher
Blackwell Publishing Inc.
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