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Acta Neuropathol. 2015 Dec;130(6):829-43. doi: 10.1007/s00401-015-1499-8. Epub 2015 Oct 24.

RCAN1 overexpression promotes age-dependent mitochondrial dysregulation related to neurodegeneration in Alzheimer's disease.

Author information

1
Center for Neural Science, New York University, New York, NY, USA.
2
Department of Integrated of Physiology, Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
3
Department of Cardiology, University of Texas-Southwestern, Dallas, TX, USA.
4
Department of Integrated of Physiology, Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA. charles.hoeffer@colorado.edu.
5
New York University School of Medicine, New York, NY, USA. charles.hoeffer@colorado.edu.
6
Linda Crnic Institute, Denver, CO, USA. charles.hoeffer@colorado.edu.

Abstract

Aging is the largest risk factor for Alzheimer's disease (AD). Patients with Down syndrome (DS) develop symptoms consistent with early-onset AD, suggesting that overexpression of chromosome 21 genes such as Regulator of Calcineurin 1 (RCAN1) plays a role in AD pathogenesis. RCAN1 levels are increased in the brain of DS and AD patients but also in the human brain with normal aging. RCAN1 has been implicated in several neuronal functions, but whether its increased expression is correlative or causal in the aging-related progression of AD remains elusive. We show that brain-specific overexpression of the human RCAN1.1S isoform in mice promotes early age-dependent memory and synaptic plasticity deficits, tau pathology, and dysregulation of dynamin-related protein 1 (DRP1) activity associated with mitochondrial dysfunction and oxidative stress, reproducing key AD features. Based on these findings, we propose that chronic RCAN1 overexpression during aging alters DRP1-mediated mitochondrial fission and thus acts to promote AD-related progressive neurodegeneration.

KEYWORDS:

Aging; Calcineurin; DRP1; Fission; Mitochondria; RCAN1

PMID:
26497675
PMCID:
PMC4782929
DOI:
10.1007/s00401-015-1499-8
[Indexed for MEDLINE]
Free PMC Article

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