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

Absalon, Sabrina, Kochanek, Dawn M., Raghavan, Venkatesan, Krichevsky, Anna M.·2013·The Journal of Neuroscience
DOI 10.1523/jneurosci.1327-13.2013
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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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  • miR-26b is upregulated in AD and activates CDK5/p25 signaling, promoting tau hyperphosphorylation, aberrant cell-cycle re-entry, and neuronal apoptosis.

    “On the other hand, miR-26b is upregulated in AD and activates CDK5/p25 signaling, promoting tau hyperphosphorylation, aberrant cell-cycle re-entry, and neuronal apoptosis (Absalon et al., 2013).”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Absalon et al., 2013

  • Disruptions in miRNA networks involving miR-219-5p, miR-338-5p, and miR-23a/b destabilize myelin maintenance, axonal metabolic support, and cytoskeletal integrity, contributing to early cognitive decline and impaired signal transmission in AD.

    “The combined actions of miR-219-5p, miR-338-5p, and miR-23a/b highlight how disruptions in miRNA networks destabilize myelin maintenance, axonal metabolic support, and cytoskeletal integrity, contributing to early cognitive decline and impaired signal transmission in AD (Absalon et al., 2013; Dugas et al., 2010; Li et al., 2018; Lin et al., 2013; Qian et al., 2018).”

    From Cell-specific MicroRNA networks orchestrate the pathogenesis of Alzheimer’s disease (2026) · cites this paper as Absalon et al., 2013

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Cited by

Sorted by citations

Authors
Absalon, S., Kochanek, D. M., Raghavan, V., & Krichevsky, A. M.
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2013-09-11
Volume
33
Issue
37
Pages
14645-14659
ISSN
  • 0270-6474
  • 1529-2401
DOI
10.1523/jneurosci.1327-13.2013
Cited by
259
References
7
Language
en
Licence
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 181 d)

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