MicroRNA-98 induces an Alzheimer’s disease-like disturbance by targeting insulin-like growth factor 1

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by extracellular senile plaques and intracellular neurofibrillary tangles. Many microRNAs (miRs) participate in regulating amyloid β (Aβ) formation and the metabolism of tau protein in the process of AD, and some are up-regulated in AD patients or transgenic models of AD. However, the role of miR-98 in AD remains unclear. Here, we showed that the expression of miR-98 was negatively correlated with the insulin-like growth factor 1 (IGF-1) protein level in APP/PS1 mice. MiR-98 target sites in IGF-1 were confirmed by luciferase assay in HEK293 cells. Overexpression of miR-98 in N2a/APP cells down-regulated the IGF-1 protein level and promoted Aβ production, whereas inhibition of miR-98 in N2a/APP cells up-regulated the IGF-1 protein level and suppressed Aβ production. Furthermore, overexpression of miR-98 in N2a/WT cells increased the phosphorylation of tau, whereas inhibition of miR-98 reduced it. These results suggest that miR-98 increases Aβ formation and tau phosphorylation by inhibiting the translation of IGF-1, which might provide a therapeutic strategy for AD.

miR-126 contributes to Parkinson's disease by dysregulating the insulin-like growth factor/phosphoinositide 3-kinase signaling

“…For example, 11 miRNAs that potentially target IRS-1 were increased in the mitochondrial-stressed hepatocytes (Ryu, et al, 2011), and 4 of them were elevated in the PD DA neurons in our study. Other examples include miR-470, -669b, and -681, which were recently identified as potential suppressors of IGF-1R and AKT in the hippocampus of aged Ames dwarf and growth hormone receptor knock out mice (Liang, et al, 2011), and miR-7 and miR-98, which inhibit IGF-1/AKT signaling by targeting IRS-1 in glioblastoma or N2A cells, respectively (Hu, et al, 2013, Kefas, et al, 2008). In our miRNA profiles, miR-7, -470, -669b, and 681 were not included in the TaqMan® Human MicroRNA A Array v2.0., and miR-98 was expressed below detection threshold.…”

MiR-126 Regulates Growth Factor Activities and Vulnerability to Toxic Insult in Neurons

“…miR-126 may also not exclusively regulate PI3K signaling. For example, in the hippocampus of aged Ames dwarf and growth hormone receptor knock out mice, miR-470, -669b, and -681 were identified as potential suppressors of IGF-1R and AKT [17]; in glioblastoma cells miR-7 inhibits IGF-1/AKT signaling by targeting IRS-1 [83]; and in transfected N2A cells that stably express APP, overexpression of miR-98 downregulates its target IGF-1 and indirectly increases Aβ production and Tau phosphorylation [84]. In addition, miR-320, which is expressed in neurons, including pigmented neurons in the substantia nigra [22], influences IGF-1 signaling through regulation of IGF-1/2, IGF-1R, phosphoinositide-3-kinase regulatory subunit 1 (p85α; PIK3R1), and the glucose transporter 4 (SLC2A4) [85,86].…”

Sirtuins and Their Roles in Brain Aging and Neurodegenerative Disorders

“…IIS can suppress Aβ production [163] and resulting tissue damage [164] although its full role in AD is still unclear [165, 166]. Deeper understanding is necessary as it may become an attractive target in the future treatment of AD and PD [167].…”