Title | miR-302 Attenuates Amyloid-β-Induced Neurotoxicity through Activation of Akt Signaling. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Li, H-H, Lin, S-L, Huang, C-N, Lu, F-J, Chiu, P-Y, Huang, W-N, Lai, T-J, Lin, C-L |
Journal | J Alzheimers Dis |
Volume | 50 |
Issue | 4 |
Pagination | 1083-98 |
Date Published | 2016 |
ISSN | 1875-8908 |
Keywords | Aged, Aged, 80 and over, Amyloid beta-Peptides, Cell Line, Tumor, Cell Survival, Female, Glycogen Synthase Kinase 3 beta, Heme Oxygenase-1, Humans, Insulin, Male, Membrane Potential, Mitochondrial, MicroRNAs, Neurons, NF-E2-Related Factor 2, Oxidative Stress, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Reactive Oxygen Species, Ribonucleoproteins |
Abstract | Deficiency of insulin signaling has been linked to diabetes and ageing-related neurodegenerative diseases such as Alzheimer's disease (AD). In this regard, brains exhibit defective insulin receptor substrate-1 (IRS-1) and hence result in alteration of insulin signaling in progression of AD, the most common cause of dementia. Consequently, dysregulation of insulin signaling plays an important role in amyloid-β (Aβ)-induced neurotoxicity. As the derivation of induced pluripotent stem cells (iPSC) involves cell reprogramming, it may provide a means for regaining the control of ageing-associated dysfunction and neurodegeneration via affecting insulin-related signaling. To this, we found that an embryonic stem cell (ESC)-specific microRNA, miR-302, silences phosphatase and tensin homolog (PTEN) to activate Akt signaling, which subsequently stimulates nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) elevation and hence inhibits Aβ-induced neurotoxicity. miR-302 is predominantly expressed in iPSCs and is known to regulate several important biological processes of anti-oxidative stress, anti-apoptosis, and anti-aging through activating Akt signaling. In addition, we also found that miR-302-mediated Akt signaling further stimulates Nanog expression to suppress Aβ-induced p-Ser307 IRS-1 expression and thus enhances tyrosine phosphorylation and p-Ser 473-Akt/p-Ser 9-GSK3β formation. Furthermore, our in vivo studies revealed that the mRNA expression levels of both Nanog and miR-302-encoding LARP7 genes were significantly reduced in AD patients' blood cells, providing a novel diagnosis marker for AD. Taken together, our findings demonstrated that miR-302 is able to inhibit Aβ-induced cytotoxicity via activating Akt signaling to upregulate Nrf2 and Nanog expressions, leading to a marked restoration of insulin signaling in AD neurons. |
DOI | 10.3233/JAD-150741 |
Alternate Journal | J. Alzheimers Dis. |
PubMed ID | 26890744 |