Abeta-induced cerebral endothelial cell death via LKB1-AMPK-p38MAPK cascade

Yu-Fan Chuang, Ming-Jen Hsu

Research output: Contribution to journalArticlepeer-review


Background: Accumulation of amyloid-beta peptide (Abeta) in senile plaques in the brain has been implicated in the pathogenesis of Alzheimer's disease (AD). Abeta also deposits in brain blood vessels, leading to the development of cerebral amyloid angiopathy (CAA). CAA increased vulnerability to hemorrhagic and ischemic strokes in the elderly. The molecular mechanism underlying Abeta-induced vasculopathy has not been fully delineated. We previously demonstrated that Abeta-induced cerebral endothelial cell (CEC) death is secondary to the activation of PP2A-ASK1-MKK3/6-p38MAPK signaling cascade and subsequently p53 phosphorylation and Bax expression. In this study, we aim to further explore the mechanisms underlying Abeta-induced CEC death.

Methods: Effects of Abeta on cell viability, transcription factor activation, signaling molecule modifications were analyzed by the MTT assay, immunoblotting, reporter assay and uses of dominant negative (DN) constructs and siRNAs.

Results: Abeta caused increases in LKB1 and AMPK phosphorylation in CECs. LKB1-AMPK signaling blockade also reduced Abeta's enhancing effects in p38MAPK and p53 phosphorylation. On the other hand, Abeta also caused increases in p53 acetylation, miR34a level, p53-luciferase and miR34a-promoter luciferase activities. The expression of SIRT1, a miR34a target, was decreased in CECs after Abeta exposure. Furthermore, transfection with SIRT1 inhibited Abeta-induced p53 acetylation.

Conclusions: Abeta-induced p53 activation and CEC death may involve LKB1-AMPK-p38MAPK signaling cascade. Abeta also activates p53-miR34a-SIRT cascade, leading to p53 acetylation and contributing to the vicious cycle of activating p53-mediated cell death in CECs.
Original languageChinese (Traditional)
Pages (from-to)PO1-1-60
JournalProceedings for Annual Meeting of The Japanese Pharmacological Society
Publication statusPublished - 2018

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