MicroRNA‐326 decreases tau phosphorylation and neuron apoptosis through inhibition of the JNK signaling pathway by targeting VAV1 in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive and age-related neurological dysfunction.Abundant data have profiled microRNA (miR) patterns in healthy, aging brain, and in the moderate and late-stages of AD. Herein, this study aimed to explore whether miR-326 could influence neuron apoptosis in AD mice and how miR-326 functions in this process. The candidate differentially expressed gene VAV1 was obtained by microarray analysis, and miRNAs that could regulate VAV1 candidate gene were predicted. Luciferase activity determination confirmed VAV1 as a target gene of miR-326. AD mice models were established for investigating the effect of miR-326 on AD mice. The overexpression of miR-326 contributed to decreased time of the mice to find the platform and the escape latency and increased residence time on the target area. Besides, elevation of miR-326 decreased Aβ deposition and contents of Aβ 1-40 and Aβ 1-42 . Moreover, miR-326 overexpression increased neuron cell ability, mediated cell entry, and inhibited neuron apoptosis via JNK signaling pathway. Of crucial importance, miR-326 negatively regulated the expression of VAV1, inhibited tau phosphorylation, and blocked the activation of the JNK signaling pathway. Taken together these observations, we demonstrate that miR-326 improves cognitive function of AD mice and inhibits neuron apoptosis in AD mice through inactivation of the JNK signaling pathway by targeting VAV1. Based on those findings, miR-326 might exert promise as target for the treatment of AD.

Nicotine abolishes memory‐related synaptic strengthening and promotes synaptic depression in the neurogenic dentate gyrus of miR‐132/212 knockout mice

“…For example, miRNAs are critical for neural development 21 and adult neurogenesis, 14,18,19 and memory‐related synaptic plasticity 22,23 . Dysregulation of miRNAs activity is further associated with a wide variety of severely debilitating human neurodegenerative conditions such as epilepsy, 24–26 Alzheimer's 27–35 and Parkinson's diseases 11 …”

Current Status of microRNA-Based Therapeutic Approaches in Neurodegenerative Disorders

“…Moreover, in a consequent in vivo assay, tail vein injection of a recombinant lentivirus expressing miR-107 was applied to mice treated with 6-OHDA, resulting in the up-regulation of miR-107 and consequently repressing 6-OHDA effects. The same delivery mechanism was used by other workers to introduce miR-326 lentiviral vectors into mice, and after analyzing the brain tissue, it was observed that overexpression of miR-326 was favorable, since it inhibited JNK signaling pathway, leading to an improvement of cognitive function; accumulation of Aβ was reduced and VAV1 protein expression was restrained [ 48 ].…”

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

“…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). Elevating the levels of microRNA-195 diminishes tau hyperphosphorylation and Aβ burden in ApoE4 +/+ mice (131).…”