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

Hyun ju Lee, Seong Gak Jeon, Jieun Kim, Ri Jin Kang, Seong Min Kim, Kyung Min Han, Hyun Hee Park, Ki taek Kim, You Me Sung, Hye Yeon Nam, Young Ho Koh, Minseok Song, Kyoungho Suk, Hyang Sook Hoe

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish
Article numbere13332
JournalAging Cell
Volume20
Issue number3
DOIs
StatePublished - Mar 2021

Keywords

  • 5xFAD mice
  • Alzheimer's disease
  • PS19 mice
  • amyloid beta
  • ibrutinib
  • neuroinflammation
  • spinogenesis
  • tau

Fingerprint

Dive into the research topics of 'Ibrutinib modulates Aβ/tau pathology, neuroinflammation, and cognitive function in mouse models of Alzheimer's disease'. Together they form a unique fingerprint.

Cite this