miR-23b-3p rescues cognition in Alzheimer?s disease by reducing tau phosphorylation and apoptosis via GSK-3B signaling pathways
MOLECULAR THERAPY-NUCLEIC ACIDS(2022)
摘要
Dysregulated microRNA (miRNA) expression in the brain can contribute to cognitive dysfunction and aberrant tau hyperphosphorylation in Alzheimer???s disease (AD). Several studies have reported a role for microRNA-23b-3p (miR-23b-3p) in various neurologic disorders; however, its involvement in cognitionrelated functions remains unclear. In the present study, we investigated the potential therapeutic effects and mechanisms of miR23b-3p in AD. miRNA profiles in the cortex of amyloid precursor PS1 mice) demonstrated that miR-23b-3p was reduced. This decrease was verified in APPswe cells, SAMP8 mouse brains, and plasma from AD patients. Furthermore, glycogen synthase kinase-3ll (GSK-3ll), a major tau kinase implicated in tau pathology, was identified as a target of miR-23b-3p. Functional in vivo studies demonstrated that intracerebroventricular delivery of miR-23b-3p in APP/PS1 mice ameliorated cognitive deficits, histopathological changes, and tau phosphorylation immunoreactivity at several sites by inhibiting GSK-3ll expression and activation. Similarly, the upregulation of miR-23b-3p in APPswe cells inhibited GSK-3ll-mediated tau hyperphosphorylation, All1-42 generation, and neuronal apoptosis, resulting in the suppression of the GSK-3ll/p-tau and Bax/caspase-3 pathways. Collectively, our findings strongly support the hypothesis that miR-23b-3p plays a neuroprotective role in AD, thereby identifying miR23b-3p as a promising therapeutic target for AD.
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关键词
MT: Oligonucleotides: Therapies and Applications,Alzheimer’s disease,cognition,glycogen synthase kinase-3β,microRNA therapy,tau protein
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