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

J Neurosci. 2013 Sep 11;33(37):14645-59. doi: 10.1523/JNEUROSCI.1327-13.2013.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / pathology
  • Alzheimer Disease* / physiopathology
  • Animals
  • Apoptosis / physiology*
  • Brain
  • Cell Cycle / physiology*
  • Cell Survival
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • E2F1 Transcription Factor / genetics
  • E2F1 Transcription Factor / metabolism
  • Embryo, Mammalian
  • Female
  • Fetus
  • Humans
  • Male
  • MicroRNAs / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats
  • Up-Regulation / physiology*
  • tau Proteins / metabolism*

Substances

  • E2F1 Transcription Factor
  • E2F1 protein, human
  • MAPT protein, human
  • MIRN26A microRNA, human
  • MicroRNAs
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • tau Proteins