MiR-191-5p Attenuates Tau Phosphorylation, Aβ Generation, and Neuronal Cell Death by Regulating Death-Associated Protein Kinase 1

Abstract

Dysregulation of microRNAs has been implicated in diverse diseases, including Alzheimer's disease (AD). in plasma/serum has been identified as a novel and promising noninvasive diagnostic biomarker for AD. However, whether miR-191-5p is involved in AD pathogenesis is largely unknown, and its levels in human AD brains are undetermined. Herein, we demonstrated that miR-191-5p downregulated tau phosphorylation at multiple AD-related sites and promoted neurite outgrowth using immunoblotting, immunofluorescence, and neurite outgrowth assays. Moreover, immunoblotting and enzyme-linked immunosorbent assays indicated that miR-191-5p decreased amyloid precursor protein phosphorylation levels and beta-amyloid (Aβ) generation. Furthermore, miR-191-5p reduced ceramide-induced neuronal cell death analyzed by trypan blue staining, the in situ cell death detection kit, and Annexin V-FITC/PI flow cytometry. Next, we verified that death-associated protein kinase 1 (DAPK1) was a direct target of miR-191-5p through the dual luciferase reporter assay and confirmed that the effects of miR-191-5p were antagonized by restoration of DAPK1 expression. Finally, the hippocampal miR-191-5p level was found to be decreased in humans with AD compared with controls and was inversely correlated with the DAPK1 expression level. Collectively, these findings suggest that miR-191-5p might exert inhibitory effects on tau phosphorylation, Aβ secretion, and neuronal cell death by directly targeting DAPK1, providing an attractive therapeutic option for AD.

Protein phosphatase 2A modulation and connection with miRNAs and natural products

“…Overexpressing miR-191-5p enhances retinoic-acid-induced differentiation of neuroblastoma cells, suggesting that retinoic acid upregulates miR-191-5p. 124 EGCG downregulates miR-191-5p in lung cancer cells. 96 Furthermore, retinoic acid induces spermatogenesis in dogs by downregulating miR-19a-3p.…”

“…141 For PP2A-inhibiting natural products, resveratrol upregulates miR-124-3p, 99 miR-17-5p, 118 miR-18a-5p, 122 miR-200c-3p, 127 and miR-383-5p (Figure 4). 147 In comparison, resveratrol downregulates miR-133b, 103 miR-141-3p, 104 miR-142-3p, 108 miR-155-5p, 112 miR-200c-3p, 129 miR-21-5p, 134 miR-34a-5p, 146 and miR-520 h. 148 Retinoic acid upregulates miR-124-3p, 100 miR-142-3p, 109 miR-155-5p, 113,114 miR-15b-3p, 115 miR-191-5p, 124 miR-21-5p, 130 miR-200a-3p, miR-200c-3p, and miR-141-3p, 105 while downregulating miR-222-3p, 136 miR-92a-3p, 149 miR-19a-3p, 125 miR-17-5p, 119 miR-17-5p, 120 and miR-18a-5p. 123 Generally, the same PP2A-modulating natural products may upregulate or downregulate various miRNAs to generate diverse cellular responses by inducing or inhibiting PP2A, as demonstrated across various studies.…”

“…miR‐191‐5p participates in retinoic acid and EGCG treatment (Table 4). Overexpressing miR‐191‐5p enhances retinoic‐acid‐induced differentiation of neuroblastoma cells, suggesting that retinoic acid upregulates miR‐191‐5p 124 . EGCG downregulates miR‐191‐5p in lung cancer cells 96 …”

Activation of transient receptor potential vanilloid 1 ameliorates tau accumulation‐induced synaptic damage and cognitive dysfunction via autophagy enhancement

“…293 cells stably overexpressing human 2N4R tau (293-hTau) were maintained as described in our previous study. 29 Mouse primary neurons were isolated and cultured according to our previous protocol, 30 and neurons on seventh day in vitro were used for compound treatment. TurboFect transfection reagent (R0533;…”

Ablation of Death-Associated Protein Kinase 1 Changes the Transcriptomic Profile and Alters Neural-Related Pathways in the Brain

“…We discovered that levels of DAPK1 are significantly increased in the hippocampi of 75% of AD patients compared to those in control subject samples [ 17 , 19 , 20 ]. Activation of DAPK1 results in Aβ pathology characteristic of AD through the amyloidogenic processing of APP, hyperphosphorylation and dysregulation of tau, and cell death by multiple pathways in AD, while DAPK1 inhibition is able to attenuate AD-related pathologies [ 8 , 17 , 19 , 20 , 29 , 30 , 31 ]. Moreover, activation of DAPK1 contributes to learning and memory deficiency, whereas inhibition of DAPK1 through deletion of the DAPK1 kinase domain ameliorates learning and memory impairment in mice [ 16 , 32 , 33 ].…”