MicroRNA-135b has a neuroprotective role via targeting of β-site APP-cleaving enzyme 1

Abstract

Abstract. MicroRNAs (miRs) are a class of endogenous small non-coding RNAs that have been revealed to negatively mediate the expression of their target genes at the post-transcriptional level. Recently, particular miRs have demonstrated an involvement in the pathogenesis of Alzheimer's disease (AD). However, the specific role of miR-135b in AD has yet to be elucidated. The present study aimed to investigate the neuroprotective role of miR-135b, in addition to its underlying mechanism. Herein, reverse transcription-quantitative polymerase chain reaction was conducted to determine miR-135b expression levels in the peripheral blood samples of patients with AD and age-matched normal controls. The data of the present study revealed that the expression levels of miR-135b were significantly reduced in the peripheral blood of AD patients compared with normal controls (P<0.01). In vitro MTT analyses identified that the overexpression of miR-135b significantly enhanced the proliferation of hippocampal cells (P<0.01). Furthermore, in vivo analysis using a Y-maze test indicated that injection with miR-135b mimics into the third ventricle of anesthetized SAMP8 mice significantly enhanced their learning and memory capacities (P<0.01). Molecular mechanism investigations identified β-site APP-cleaving enzyme 1 (BACE1) as a direct target gene of miR-135b, and the latter was identified to negatively mediate the protein expression levels of BACE1 in hippocampal cells, in addition to hippocampal tissues, of SAMP8 mice. Based on the aforementioned findings, we propose that miR-135b has a neuroprotective role via direct targeting of BACE1 and, thus, may be used for the treatment of AD.

MicroRNAs in Alzheimer’s Disease

“…Other negative regulators of BACE1 also include miR-298/328 (Boissonneault et al, 2009), microRNA-195 (Zhu et al, 2012), miR-135a (Liu et al, 2014), microRNA-135b (Zhang et al, 2016), miR-339-5p (Long et al, 2014), and miR-186 (Kim et al, 2016), all of which negatively correlated with BACE1 expression and exerted regulatory effects by binding the 3’UTR of BACE1.…”

MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties

“…APP is regulated by miR-16 [25][26][27], miR-101 [28,29], miR-153 [30,31], miR-193b [32], and miR-200b [33]. Similarly, miR-9 [21], miR-15b [34,35], miR-29a/b [21], miR-135a [33], miR-135b [36], miR-195 [37], and miR-339-5p [38] modulate BACE1 expression in different models. Tau is regulated by, among others, miR-16, miR-24c-5p, and miR-132 [39,40].…”

MicroRNA-135b-5p prevents oxygen-glucose deprivation and reoxygenation-induced neuronal injury through regulation of the GSK-3/Nrf2/ARE signaling pathway

“…Fan et al reported that miR-135b-5p protects osteoblastic cells from dexamethasone-induced apoptosis [ 29 ]. Overexpression of miR-135b-5p has a neuroprotective effect on Alzheimer’s disease by targeting the β-site APP-cleaving enzyme 1 [ 23 ]. miR-135b-5p is decreased in the hippocampus of a rat model of temporal lobe epilepsy and may be involved in the regulation of hippocampal neuron apoptosis [ 30 ].…”

“…miR-135b-5p has been reported as an anti-apoptotic miRNA [ 21 , 22 ]. A recent study has shown that miR-135b-5p has a neuroprotective effect in Alzheimer’s disease [ 23 ]. However, little is known about the role of miR-135b-5p in regulating neuronal survival during cerebral ischemia/reperfusion injury.…”