RCAN1 overexpression promotes age-dependent mitochondrial dysregulation related to neurodegeneration in Alzheimer's disease.
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.
Center for Neural Science, New York University, New York, NY, USA.
Helen
H
Wong
Department of Integrated of Physiology, Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
Josien
J
Levenga
Department of Integrated of Physiology, Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
Peter
P
Cain
Department of Cardiology, University of Texas-Southwestern, Dallas, TX, USA.
Beverly
B
Rothermel
Center for Neural Science, New York University, New York, NY, USA.
Eric
E
Klann
Department of Integrated of Physiology, Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA. charles.hoeffer@colorado.edu.|New York University School of Medicine, New York, NY, USA. charles.hoeffer@colorado.edu.|Linda Crnic Institute, Denver, CO, USA. charles.hoeffer@colorado.edu.
Charles
C
Hoeffer
D000375:Aging / Q000473:pathology / Q000502:physiology* / Q000523:psychology; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000473:pathology / Q000503:physiopathology; D034281:Dynamins / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008569:Memory Disorders / Q000473:pathology / Q000503:physiopathology; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D018384:Oxidative Stress / Q000502:physiology; D016875:tau Proteins / Q000378:metabolism
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C558298:Mapt protein, mouse; D009124:Muscle Proteins; C108612:RCAN1 protein, human; D016875:tau Proteins; C486391:Dnm1l protein, mouse; D034281:Dynamins
Aging; Calcineurin; DRP1; Fission; Mitochondria; RCAN1