Abstract
IntroductionAlzheimer’s disease (AD) is a progressive neurodegenerative dementia with the key pathological hallmarks amyloid-beta deposition and neurofibrillary tangles composed of hyperphosphorylated tau. microRNAs (miRNAs) are small non-coding RNAs that contribute to the pathogenesis of AD. In this study, we investigated the effect of the loss of miR-369 on the phosphorylation of tau protein and the activation of the kinases Fyn and serine/threonine-protein kinase 2 (SRPK2) as the upstream molecules facilitating tau phosphorylation in miR-369 knockout 3xTg-AD mice.MethodsWe generated miR-369 knockout 3xTg-AD mice and investigated their cognitive behaviors by maze tests. Real-time qPCR, western blot, and immunohistochemistry were performed to evaluate the expression of the miR-369 gene, phosphorylation of tau protein, and activation of Fyn and SRPK2. Luciferase reporter assays were applied to confirm the predicted targets of miR-369.ResultsKnocking out miR-369 in 3xTg AD mice aggravated cognitive impairment, promoted hyperphosphorylation of tau, and upregulated Fyn and SRPK2. Restoring miR-369 reversed the hyperphosphorylation of tau and downregulated Fyn and SRPK2. Additionally, miR-369 was shown to target the 3′UTRs of Fyn and SRPK2 to regulate their expression levels.ConclusionLoss of miR-369 promotes tau phosphorylation by targeting the Fyn and SRPK2 signaling pathways in AD mice, and supplementation with miR-369 might be a valuable option for AD therapeutic studies.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative dementia with the key pathological hallmarks amyloid-beta deposition and neurofibrillary tangles composed of hyperphosphorylated tau. microRNAs are small non-coding RNAs that contribute to the pathogenesis of AD
In the Barnes maze test, miR-369KO/AD mice had significantly more errors and took more time to find the targets in the trials compared with those observed for the controls (Figure 1B), which indicated that the learning ability of miR-369KO/AD mice had been impaired
The expression levels of serine/threonine-protein kinase 2 (SRPK2) and Fyn kinase were significantly upregulated in the miR369KO/AD compared to controls (Figure 2H), Fyn levels did not show statistical significance
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative dementia with the key pathological hallmarks amyloid-beta deposition and neurofibrillary tangles composed of hyperphosphorylated tau. microRNAs (miRNAs) are small non-coding RNAs that contribute to the pathogenesis of AD. We investigated the effect of the loss of miR-369 on the phosphorylation of tau protein and the activation of the kinases Fyn and serine/threonine-protein kinase 2 (SRPK2) as the upstream molecules facilitating tau phosphorylation in miR-369 knockout 3xTg-AD mice. To prove the role of miR-369 in AD pathogenesis, in the present study we applied 3xTg-AD mice with miR-369 knockout to investigate whether loss of miR-369 promotes phosphorylation of tau protein, the role of Fyn and serine/threonine-protein kinase 2 (SRPK2), which are kinases that promote phosphorylation of tau protein in AD (Lee et al, 2004; Hong et al, 2012), and affect cognitive behaviors, including Morris water maze (MWM) and Barnes maze tests. We investigated whether miR-369 can target Fyn and SRPK2 directly in cultured 293T cells using a luciferase reporter assay
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
