miR-302 Attenuates Amyloid-β-Induced Neurotoxicity through Activation of Akt Signaling

Article type: Research Article

Authors: Li, Hsin-Hua^a | Lin, Shi-Lung^b | Huang, Chien-Ning^{a; d} | Lu, Fung-Jou^a | Chiu, Pai-Yi^{a; c} | Huang, Wen-Nung^a | Lai, Te-Jen^{a; e; 1} | Lin, Chih-Li^{a; f; *}

Affiliations: [a] Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan | [b] Division of Regenerative Medicine, WJWU & LYNN Institute for Stem Cell Research, Santa Fe Springs, CA, USA | [c] Department of Neurology, Show Chwan Memorial Hospital, Changhua, Taiwan | [d] Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan | [e] Department of Psychiatry, Chung Shan Medical University Hospital, Taichung, Taiwan | [f] Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan

Correspondence: [1] Co-correspondence: Te-Jen Lai, MD, PhD, Professor, Department of Psychiatry, Chung Shan Medical University Hospital, No. 110, Sec. 1, Jianguo N. Rd., Taichung City 402, Taiwan. Tel.: +886 4 2473 9595, ext. 38836; Fax: +886 4 2471 5124; E-mail: ltj3123@ms2.hinet.net.

Correspondence: [*] Correspondence to: Chih-Li Lin, PhD, Associate Professor, Institute of Medicine, Chung Shan Medical University, No. 110, Sec. 1, Jianguo N. Rd., Taichung City 402, Taiwan. Tel.: +886 4 2473 0022, ext. 11696; Fax: +886 4 2472 3229; E-mail: dll@csmu.edu.tw.

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.

Keywords: Alzheimer’s disease, amyloid-β, insulin signaling, miR-302, Nanog, phosphatase and tensin homolog

DOI: 10.3233/JAD-150741

Journal: Journal of Alzheimer's Disease, vol. 50, no. 4, pp. 1083-1098, 2016