Loss of miR-369 Promotes Tau Phosphorylation by Targeting the Fyn and Serine/Threonine-Protein Kinase 2 Signaling Pathways in Alzheimer’s Disease Mice

Abstract

Introduction: 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. 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.Methods: We 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.Results: Knocking 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.Conclusion: Loss 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.

Targeting the miRNA-155/TNFSF10 network restrains inflammatory response in the retina in a mouse model of Alzheimer’s disease

“…The expression pattern of miRNAs has been also analyzed in AD, either in pre-clinical or clinical studies [ 38 , 39 ]. Several studies have investigated the role of a single miRNA (i.e., miR-181 [ 40 , 41 ], miR-369 [ 42 ], miR-31 [ 43 ], miR-342 [ 44 ], miR-132/212 [ 45 ], miR-34a [ 46 , 47 ], miR-155 [ 20 ], miR-146a [ 48 ]) in 3xTg-AD mice, but only a few of these studies were focused on differential expression of more than one noncoding RNA [ 49 , 50 ].…”

Contribution Value：A Indicator for Measuring the Contribution of ncRNAs to Transcriptome

“…Further, we analyzed theannotation network of KEGG pathways with P value less than 0.01 andfound that the total number of top10 C value miRNAs' target genesand their proportion in each region were larger than those of top10FC miRNAs, and top10 P value miRNAs. At the same time, we searcheda large number of literatures and got 14 skeletal muscle growthregulatory miRNAs [25][26][27][28][29][30][31][32][33][34][35][36][37][38], 6 Alzheimer's disease associatedmiRNAs [39][40][41][42], 7…”

Epigenetics: Recent Advances and Its Role in the Treatment of Alzheimer's Disease

“…MicroRNA-106b reduces tau phosphorylation induced by Aβ42 by involving the expression of Fyn (128). In 3xTg-AD mice, knocking out microRNA-369 is associated with tau hyperphosphorylation via regulating Fyn and SRPK2 signaling pathways (129). MicroRNA-326 decreases tau hyperphosphorylation and improves cognitive functions of AD through the JNK signaling pathway (130).…”