title: MiR-26b, upregulated in Alzheimer's disease, activates cell cycle entry, tau-phosphorylation, and apoptosis in postmitotic neurons.
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.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, Massachusetts 02115.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Absalon
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Kochanek
authors.forename: Venkatesan
authors.initials: V
authors.lastname: Raghavan
authors.forename: Anna M
authors.initials: AM
authors.lastname: Krichevsky
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain; D002453:Cell Cycle / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian; D005260:Female; D005333:Fetus; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation / Q000502:physiology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D050687:E2F1 Transcription Factor; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D016875:tau Proteins; C493753:E2F1 protein, human; C054369:MAPT protein, human; C528163:MIRN26 microRNA, human
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