Ya-Shuo Zhao1,2, Li-Hong Zhang1, Pan-Pan Yu1, Yu-Jing Gou1, Jing Zhao1, Lin-Hao You1, Zhan-You Wang3, Xin Zheng1, Liang-Jun Yan4, Peng Yu1, Yan-Zhong Chang1,5. 1. 1 Laboratory of Molecular Iron Metabolism, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Sciences, Hebei Normal University , Shijiazhuang, China . 2. 2 Scientific Research Center, Hebei University of Chinese Medicine , Shijiazhuang, China . 3. 3 College of Life and Health Sciences, Northeastern University , Shenyang, China . 4. 4 Department of Pharmaceutical Sciences, UNIT System College of Pharmacy, University of North Texas Health Science Center , Fort Worth, Texas. 5. 5 Instrumental Analysis Center, Hebei Normal University , Shijiazhuang, China .
Abstract
AIMS: Ceruloplasmin (CP), a ferrous oxidase enzyme, plays an important role in regulating iron metabolism and redox reactions. Previous studies showed that CP deficiency contributes to Parkinson's disease by increasing iron accumulation and oxidative stress in the substantia nigra. However, the role of CP in Alzheimer's disease (AD) is unclear. We hypothesized that the lack of CP gene expression would affect the pathogenesis and damage of AD by promoting abnormal iron levels and oxidative stress. RESULTS: AD mouse models were induced in CP knockout mouse either by injection of Aβ25-35 into the lateral ventricle of the brain or transgenic APP expression. CP levels were decreased significantly in the hippocampus of AD patients, as well as Aβ-CP+/+ and APP-CP+/+ mice. Compared to control AD mice, CP gene deletion increased memory impairment and iron accumulation, which could be associated with elevated reactive oxygen species (ROS) levels and lead to cell apoptosis mediated through the Bcl-2/Bax and Erk/p38 signaling pathways in Aβ-CP-/- and APP-CP-/- mice. In contrast, the restoration of CP expression to CP-/- mice through injection of an exogenous expression plasmid into the brain ventricle alleviated Aβ-induced neuronal damage in the hippocampus. INNOVATION: CP alterations in iron contents were mediated through DMT1(-IRE) and changes in ROS levels, which in turn attenuated the progression of AD through the Erk/p38 and Bcl-2/Bax signaling pathways. CONCLUSION: Our results show a protective role of CP in AD and suggest that regulating CP expression in the hippocampus may provide a new neuroprotective strategy for AD. Antioxid. Redox Signal. 28, 1323-1337.
AIMS: Ceruloplasmin (CP), a ferrous oxidase enzyme, plays an important role in regulating iron metabolism and redox reactions. Previous studies showed that CP deficiency contributes to Parkinson's disease by increasing iron accumulation and oxidative stress in the substantia nigra. However, the role of CP in Alzheimer's disease (AD) is unclear. We hypothesized that the lack of CP gene expression would affect the pathogenesis and damage of AD by promoting abnormal iron levels and oxidative stress. RESULTS:ADmouse models were induced in CP knockout mouse either by injection of Aβ25-35 into the lateral ventricle of the brain or transgenic APP expression. CP levels were decreased significantly in the hippocampus of ADpatients, as well as Aβ-CP+/+ and APP-CP+/+ mice. Compared to control ADmice, CP gene deletion increased memory impairment and iron accumulation, which could be associated with elevated reactive oxygen species (ROS) levels and lead to cell apoptosis mediated through the Bcl-2/Bax and Erk/p38 signaling pathways in Aβ-CP-/- and APP-CP-/- mice. In contrast, the restoration of CP expression to CP-/- mice through injection of an exogenous expression plasmid into the brain ventricle alleviated Aβ-induced neuronal damage in the hippocampus. INNOVATION: CP alterations in iron contents were mediated through DMT1(-IRE) and changes in ROS levels, which in turn attenuated the progression of AD through the Erk/p38 and Bcl-2/Bax signaling pathways. CONCLUSION: Our results show a protective role of CP in AD and suggest that regulating CP expression in the hippocampus may provide a new neuroprotective strategy for AD. Antioxid. Redox Signal. 28, 1323-1337.
Authors: Fan Liu; Zhuo Zhang; Lin Zhang; Ruo-Ni Meng; Jia Gao; Ming Jin; Ming Li; Xiao-Peng Wang Journal: Brain Behav Date: 2022-02-24 Impact factor: 2.708