MiR-124 acts as a target for Alzheimer’s disease by regulating BACE1

Abstract

Although large numbers of microRNAs (miRNAs) expressed in Alzheimer disease (AD) have been detected, their functions and mechanisms of regulation remain to be fully clarified. Beta-site Amyloid precursor protein Cleaving Enzyme 1 (BACE1) has been one of the prime therapeutic targets for AD. Here, we identified that miR-124 levels are gradually decreased in AD. In addition, we demonstrated that miR-124 suppresses BACE1 expression by directly targeting the 3′UTR of Bace1 mRNA in vitro. Inhibition of miR-124 significantly increased BACE1 levels in neuronal cells. In contrast, miR-124 overexpression significantly suppressed BACE1 expression in cells. And finally we determined that downregulation of miR-124 alleviated Aβ-induced viability inhibition and decreased apoptosis in SH-SY5Y cells. Our results demonstrated that miR-124 is a potent negative regulator of BACE1 in the cellular AD phenotype and might be involved in the pathogenesis of AD.

Small GTPases of the Ras and Rho Families Switch on/off Signaling Pathways in Neurodegenerative Diseases

“…Thus, in the presence of Aβ or hypoxia, miR-124 inhibition provokes an increase in BACE1 levels and, therefore, in the production of toxic Aβ [ 58 ]. Additionally, it is important to highlight that AD patients express low levels of miR-124 [ 59 ].…”

Chronic Regulation of miR-124-3p in the Perilesional Cortex after Experimental and Human TBI

“…Unexpectedly, we found that the sham-operation (i.e., craniotomy) also affects the miR-124-3p level, indicating that miR-124-3p could be highly responsive to skull and brain surgery. Interestingly, miR-124-3p is also downregulated in the cortex of mice with frontotemporal dementia [64], in the frontal cortex of patients with a behavioral variant of frontotemporal dementia [64], in patients with sporadic Alzheimer disease [65], and in cellular models of Parkinson disease [66] and Alzheimer disease [67]. Together, these findings indicate that miR-124-3p downregulation is broadly connected to brain injury and neurodegeneration, independent of the etiology.…”

“…A study conducted on human SH-SY5Y cells showed that inhibiting miR-124-3p promoted apoptosis through the AMPK/mTOR pathway [71]. Moreover, miR-124-3p directly targets beta-secretase 1 [65,67], which has a crucial role in the formation of beta-amyloid, indicating that miR-124-3p downregulation contributes to the pathologic hallmarks of Alzheimer's disease.…”

The Potential Role of MicroRNA-124 in Cerebral Ischemia Injury

“…Regulatory factor X1 RFX1 Anti-Aβ deposition Decreased miR-124 represses ApoE-dependent Aβ uptake by targeting and upregulating RFX1 [34] cAMP-response element binding protein CREB Suppressing synaptic plasticity Decreased miR-124 increases the expression of CREB and subsequent BDNF synthesis [45] Tyrosine-protein phosphatase non-receptor type 1 PTPN1 Suppressing synaptic plasticity Downregulating the expression of PTPN1 [46] Beta-site Amyloid precursor protein Cleaving Enzyme 1 BACE1 Anti-Aβ deposition Decreased miR-124 upregulates BACE1 level [47] Caveolin-1 Cav-1 Inhibiting hyperphosphorylation of tau Repressing the expression of Cav-1, which further activates PI3K/AKT/GSK3β signaling pathway [35] Epilepsy cAMP-response element-binding protein 1 CREB1 Anti-neuronal excitability Repressing the expression of CREB1 [32] CCAAT/enhancer-binding protein alpha C/EBPα Anti-epileptogenic Downregulating C/EBPα level, which then inhibits the expression and activity of NRSF [54] Bcl-2-like 13 Bcl2L13 Anti-apoptosis Diminishing the expression of Bcl2L13, which further represses the activation of caspase-3 [55] 2.1. MiR-124 and Ischemic Stroke…”

“…More importantly, miR-124/BACE1 axis has been considered as a novel target in AD treatment [108]. An et al observed that miR-124 was a negative regulator of BACE1 by directly targeting the 3'UTR of BACE1 mRNA, and the downregulation of miR-124 attenuated Aβ-induced apoptosis and cell viability inhibition in SH-SY5Y cells [47]. Furthermore, Fang et al found the expression of BACE1 could be upregulated on the consequence of the downregulation of miR-124, and further exacerbated amyloid pathology, resulting in the promotion of endogenous Aβ production and Aβ neurotoxicity-induced cell death [93].…”