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.

Notch signaling in response to excitotoxicity induces neurodegeneration via erroneous cell cycle reentry

“…29 Activation of E2F1-mediated transcription in neurons upon injury, AD and PD has been reported before and has been associated to neuronal damage. 9,45,46 In our study, we observe that upon KA, the Ccnd1/Rb/E2F1 axis is positively regulated leading to an increase in transcription of PCNA and Cyclin E1 in neurons. Such regulation was absent in the RBPJKcKOs.…”

“…[3][4][5][6] Recent studies have proposed some important molecular players involved in CCR in neurons. [7][8][9][10] Yet, a precise molecular pathway triggered by diverse neurodegenerative stimuli that leads to CCR in neurons remains unidentified.…”

MicroRNA-613 regulates the expression of brain-derived neurotrophic factor in Alzheimer's disease

“…Recently, several miRNAs have been found to be related to AD pathogenesis by affecting the expression of function of AD-relevant molecules such as amyloid precursor protein (APP) (7), β-site amyloid precursor protein cleaving enzyme 1 (BACE1) (8) or Tau (9,10). Measurements of miRNAs in blood and cerebrospinal fluid (CSF) have become a novel diagnostic tool for various neurological diseases, including AD.…”

microRNAs That Promote or Inhibit Memory Formation in Drosophila melanogaster

“…For example, Xu et al (2008) demonstrated that miR124a ectopic expression decreases dendritic branching, an effect rescued by the loss of dFMRP expression. In addition, miRNAs in circulating blood are candidate biomarkers for early phases of neurological disease De Smaele et al 2010;Absalon et al 2013). Moreover, miRNAs may offer promise as therapeutics for disease states using multiple approaches (Sayed and Abdellatif 2011;Im and Kenny 2012).…”