title: Intranasal deferoxamine attenuates synapse loss via up-regulating the P38/HIF-1α pathway on the brain of APP/PS1 transgenic mice.
abstract: The widely recognized neuroprotective effect of iron chelators is contributed by their ability to prevent reactive oxygen species (ROS) generation via the Fenton reaction, which sequesters redox-active Fe. An additional neuroprotective mechanism of iron-chelating compounds is to regulate the transcriptional activator hypoxia-inducible factor 1α (HIF-1α). In the present study, we observed that intranasal administration of deferoxamine decreased beta-amyloid (Aβ) deposition and rescued synapse loss in the brain of Aβ precursor protein and presenilin-1 (APP/PS1) double transgenic mice. We found that deferoxamine (DFO) up-regulated HIF-1α mRNA expression and its protein level, and further induced the proteins that are encoded from HIF-1-adaptive genes, including transferrin receptor (TFR), divalent metal transporter 1 (DMT1), and brain-derived neurotrophic factor (BDNF). The effects of DFO on the induction and stabilization of HIF-1α were further confirmed in vitro. This was accompanied by a decrease of Fe in the CA3 region of the hippocampus. Western blotting studies revealed that DFO differentially enhanced the phosphorylation of mitogen-activated protein kinase (MAPK)/P38 kinase in vitro and in vivo. The results suggest that the DFO may up-regulate several HIF-1-dependent neuroprotective-adaptive genes in AD via activating P38/HIF-1α pathway, which may serve as important therapeutic targets to the disease.
authors.affiliation: College of Life and Health Sciences, Northeastern University Shenyang, China.
authors.forename: Chuang
authors.initials: C
authors.lastname: Guo
authors.affiliation: Department of Anatomy, Hebei United University Tangshan, China.
authors.forename: Yu-Xin
authors.initials: YX
authors.lastname: Zhang
authors.affiliation: College of Life and Health Sciences, Northeastern University Shenyang, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: College of Life and Health Sciences, Northeastern University Shenyang, China.
authors.forename: Man-Li
authors.initials: ML
authors.lastname: Zhong
authors.affiliation: College of Life and Health Sciences, Northeastern University Shenyang, China.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Yang
authors.affiliation: College of Life and Health Sciences, Northeastern University Shenyang, China.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Hao
authors.affiliation: College of Life and Health Sciences, Northeastern University Shenyang, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Chai
authors.affiliation: College of Life and Health Sciences, Northeastern University Shenyang, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Zhang
keywords: Alzheimer’s disease; deferoxamine; hypoxia inducible factor; iron; synapse; transgenic mouse