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Overexpression of apoptosis inducing factor aggravates hypoxic-ischemic brain injury in neonatal mice

Journal article
Authors Tao Li
Kenan Li
Shan Zhang
Yafeng Wang
Yiran Xu
S. J. F. Cronin
Yanyan Sun
Yaodong Zhang
Cuicui Xie
Juan Rodriguez
Kai Zhou
Henrik Hagberg
Carina Mallard
Xiaoyang Wang
J. M. Penninger
G. Kroemer
K. Blomgren
Changlian Zhu
Published in Cell death & disease
Volume 11
Issue 1
Pages 18
ISSN 2041-4889
Publication year 2020
Published at Institute of Neuroscience and Physiology
Institute of Clinical Sciences, Department of Obstetrics and Gynecology
Pages 18
Language en
Links dx.doi.org/10.1038/s41419-020-2280-...
Keywords neuronal cell-death, poly(adp-ribose) polymerase, therapeutic, hypothermia, mitochondrial dynamics, factor leads, aif, encephalopathy, neuroprotection, hippocampus, inhibition, Cell Biology
Subject categories Clinical Medicine

Abstract

Apoptosis inducing factor (AIF) has been shown to be a major contributor to neuron loss in the immature brain after hypoxia-ischemia (HI). Indeed, mice bearing a hypomorphic mutation causing reduced AIF expression are protected against neonatal HI. To further investigate the possible molecular mechanisms of this neuroprotection, we generated an AIF knock-in mouse by introduction of a latent transgene coding for flagged AIF protein into the Rosa26 locus, followed by its conditional activation by a ubiquitously expressed Cre recombinase. Such AIF transgenic mice overexpress the pro-apoptotic splice variant of AIF (AIF1) at both the mRNA (5.9 times higher) and protein level (2.4 times higher), but not the brain-specific AIF splice-isoform (AIF2). Excessive AIF did not have any apparent effects on the phenotype or physiological functions of the mice. However, brain injury (both gray and white matter) after neonatal HI was exacerbated in mice overexpressing AIF, coupled to enhanced translocation of mitochondrial AIF to the nucleus as well as enhanced caspase-3 activation in some brain regions, as indicated by immunohistochemistry. Altogether, these findings corroborate earlier studies demonstrating that AIF plays a causal role in neonatal HI brain injury.

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