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      MiR-26b, upregulated in Alzheimer's disease, activates cell cycle entry, tau-phosphorylation, and apoptosis in postmitotic neurons.

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          Abstract

          MicroRNA (miRNA) functions in the pathogenesis of major neurodegenerative diseases such as Alzheimer's disease (AD) are only beginning to emerge. We have observed significantly elevated levels of a specific miRNA, miR-26b, in the defined pathological areas of human postmortem brains, starting from early stages of AD (Braak III). Ectopic overexpression of miR-26b in rat primary postmitotic neurons led to the DNA replication and aberrant cell cycle entry (CCE) and, in parallel, increased tau-phosphorylation, which culminated in the apoptotic cell death of neurons. Similar tau hyperphosphorylation and CCE are typical features of neurons in pre-AD brains. Sequence-specific inhibition of miR-26b in culture is neuroprotective against oxidative stress. Retinoblastoma protein (Rb1), a major tumor suppressor, appears as the key direct miR-26b target, which mediates the observed neuronal phenotypes. The downstream signaling involves upregulation of Rb1/E2F cell cycle and pro-apoptotic transcriptional targets, including cyclin E1, and corresponding downregulation of cell cycle inhibitor p27/Kip1. It further leads to nuclear export and activation of Cdk5, a major kinase implicated in tau phosphorylation, regulation of cell cycle, and death in postmitotic neurons. Therefore, upregulation of miR-26b in neurons causes pleiotropic phenotypes that are also observed in AD. Elevated levels of miR-26b may thus contribute to the AD neuronal pathology.

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          Author and article information

          Journal
          J. Neurosci.
          The Journal of neuroscience : the official journal of the Society for Neuroscience
          Society for Neuroscience
          1529-2401
          0270-6474
          Sep 11 2013
          : 33
          : 37
          Affiliations
          [1 ] Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, Massachusetts 02115.
          Article
          33/37/14645
          10.1523/JNEUROSCI.1327-13.2013
          3810537
          24027266

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