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NOX4 negatively regulates memory functions in APP/PS1 mice
Author(s) -
Zhu Xiaolei,
Tao Wenyuan,
Yu Linjie,
Jin Jiali,
Xu Yun
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.038198
Subject(s) - nox4 , oxidative stress , morris water navigation task , hippocampus , hippocampal formation , neurotoxicity , long term potentiation , pathogenesis , lipid peroxidation , genetically modified mouse , amyloid precursor protein , blot , chemistry , endocrinology , medicine , alzheimer's disease , transgene , biochemistry , toxicity , nadph oxidase , disease , receptor , gene
Background Excessive oxidative stress plays a critical role in the pathogenesis and progression of Alzheimer's disease (AD). Nox4 is constitutively active and widely expressed in the brains, and inhibition of Nox4 decreases the level of ROS and oxidative stress. Emerging evidence has shown that NOX4 inhibition protects against stoke and traumatic brain injury. However, the role of NOX4 in the pathogenesis of AD is not defined. Method Male APPswe/PS1dE9 (APP/PS1) transgenic mice, NOX4 ‐/‐ mice and wild type C57BL/6 (B6) littermates were obtained from the Model Animal Research Center of Nanjing University. GLX351322 (5 mg/kg/day, MedChemExpress, USA), was intraperitoneally injected to APP/PS1 mice for 4 weeks followed by the behavior tests. The memory function was examined by Novel‐object recognition (NOR), Fear condition (FC) and Morris water maze (MWM) tests. The amyloid load was determined by immuofluorescence assay (IFA) and ELISA. Synaptic transmission was examined by hippocampal LTP induction and synaptic proteins were determined by IFA and western blotting. The markers of lipid peroxidation 4‐HNE, protein oxidation 3‐NT, and DNA oxidation 8‐OHdG were detected using the corresponding ELISA kits. The level of ROS and H 2 O 2 was measured using the commercialized kits. Result Nox4 was mainly expressed in neurons in the central nerve system, and Nox4 inhibition by GLX351322 protected against Aβ 1‐42 induced neurotoxicity. In addition, GLX351322 treatment attenuated memory deficits and synaptic dysfunction of APP/PS1 mice, and decreased the amyloid load and oxidative stress in the hippocampus of APP/PS1 mice. Furthermore, Nox4 knockout APP/PS1 mice showed improved memory functions and decreased amyloid load and oxidative stress, which was consistent with the results of GLX351322. Conclusion Our results have demonstrated that NOX4 inhibition or knockout attenuated memory deficits in APP/PS1 mice, suggesting that NOX4 might be a potential target for AD treatment.