Abstract
MicroRNAs are small non-coding RNAs that repress the expression of their target proteins. The roles of microRNAs in the development of Alzheimer's disease (AD) are not clear. In this study we show that miR-200c represses the expression of PTEN protein. PTEN downregulation by miR-200c supports the survival and differentiation of cultured neurons. AD is a progressive neurodegenerative disease signified by beta amyloid (Aβ) peptide aggregation and deposition. In a mouse model of AD that is induced by APPswe and PS1ΔE9 double transgenes, we found Aβ deposition results in neuronal ER stress that induces miR200c. Pharmacological blockade of ER stress inhibited Aβ-induced miR-200c overexpression in AD brains. MiR-200c was detected in the serum of both AD mice and human AD patients. These findings suggest that miR-200c functions as part of the neuronal cell-intrinsic adaptive machinery, and supports neuronal survival and differentiation in response to Aβ induced ER-stress by downregulating PTEN.
Highlights
Alzheimer’s disease (AD) is one of most common neurodegenerative diseases affecting about 35 million people around the world (Querfurth and LaFerla, 2010), accounting for up to 70% of total dementia cases
Since miR-200c is dysregulated in the AD brain and is important for neuronal survival at least in part through regulating the expression of PTEN, we examined the role of miR-200c in beta amyloid peptide (Aβ)-induced neuronal cell death
We found Aβ peptide treatment induces phosphorylation of PERK and eIF2 α and upregulates miR-200c expression, which were observed in APP/PS1 mouse brains (4–6 months old)
Summary
Alzheimer’s disease (AD) is one of most common neurodegenerative diseases affecting about 35 million people around the world (Querfurth and LaFerla, 2010), accounting for up to 70% of total dementia cases. How Aβ-induced ER stress leads to neuronal dysfunction still remains unknown. Protein translation in neurons is tightly regulated by miRs. Since numerous key proteins have been identified as targets of miRs, it is well established that miRs are the most important fine-tuning regulators for many cellular process such as cell proliferation, differentiation, migration, apoptosis and senescence. By genome-wide analysis of microRNA signature in the APPswe/PS1 E9 double transgenic mice that harbor overexpressed Aβ peptide in the brain, we previously identified a series of miRs whose expressions were dysregulated during AD development (Luo et al, 2014). We identified PTEN as a target of miR-200 family in neuronal cells. We provided evidence showing that upregulation of miR-200 family by ER stress exhibited protective roles via PTEN suppression in early phase of AD
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