Related Experiment Video
Updated: Dec 8, 2025
Analysis of Learning and Memory Ability in an Alzheimer's Disease Mouse Model using the Morris Water Maze
Published on: October 29, 2019
miR-204-3p/Nox4 Mediates Memory Deficits in a Mouse Model of Alzheimer's Disease
Wenyuan Tao1, Linjie Yu1, Shu Shu1
1Department of Neurology, Drum Tower Hospital, Medical School and The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu 210008, PR China; Institute of Brain Sciences, Nanjing University, Nanjing, Jiangsu 210093, PR China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, PR China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu 210008, PR China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, Jiangsu 210008, PR China.
Abstract:
Alzheimer's disease (AD) is the most common neurodegenerative disorder leading to dementia in the elderly, and the mechanisms of AD are not fully defined. MicroRNAs (miRNAs) have been shown to contribute to memory deficits in AD. In this study, we identified that miR-204-3p was downregulated in the hippocampus and plasma of 6-month-old APPswe/PS1dE9 (APP/PS1) mice. miR-204-3p overexpression attenuated memory and synaptic deficits in APP/PS1 mice. The amyloid levels and oxidative stress were decreased in the hippocampus of APP/PS1 mice after miR-204-3p overexpression. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4) was a target of miR-204-3p, and Nox4 inhibition by GLX351322 protected neuronal cells against Aβ1-42-induced neurotoxicity. Furthermore, GLX351322 treatment rescued synaptic and memory deficits, and decreased oxidative stress and amyloid levels in the hippocampus of APP/PS1 mice. These results revealed that miR-204-3p attenuated memory deficits and oxidative stress in APP/PS1 mice by targeting Nox4, and miR-204-3p overexpression and/or Nox4 inhibition might be a potential therapeutic strategy for AD treatment.
Insights
MicroRNA-204-3p (miR-204-3p) is reduced in Alzheimer's disease (AD) models. Restoring miR-204-3p or inhibiting its target, NADPH oxidase 4 (Nox4), improved memory and reduced AD pathology.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Alzheimer's disease (AD) is a leading cause of dementia, with underlying mechanisms still under investigation.
- MicroRNAs (miRNAs) play a role in AD pathogenesis, particularly in cognitive decline.
- Specific miRNA dysregulation in AD brains and plasma requires further elucidation.
Purpose of the Study:
- To investigate the role of miR-204-3p in Alzheimer's disease.
- To identify the molecular targets and therapeutic potential of miR-204-3p in AD models.
Main Methods:
- Quantification of miR-204-3p in the hippocampus and plasma of APPswe/PS1dE9 (APP/PS1) mice.
- Assessment of cognitive and synaptic function following miR-204-3p overexpression in APP/PS1 mice.
- Analysis of amyloid-beta (Aβ) levels, oxidative stress markers, and NADPH oxidase 4 (Nox4) expression.
- Evaluation of the therapeutic effects of Nox4 inhibition using GLX351322 in vitro and in vivo.
Main Results:
- miR-204-3p was found to be downregulated in the hippocampus and plasma of APP/PS1 mice.
- Overexpression of miR-204-3p ameliorated memory and synaptic deficits in APP/PS1 mice.
- miR-204-3p overexpression reduced amyloid burden and oxidative stress in the hippocampus.
- Nox4 was identified as a direct target of miR-204-3p, and its inhibition protected neurons from Aβ toxicity.
- GLX351322 treatment mimicked the protective effects of miR-204-3p, rescuing cognitive deficits and reducing AD pathology.
Conclusions:
- miR-204-3p plays a protective role in Alzheimer's disease by targeting Nox4.
- Restoring miR-204-3p levels or inhibiting Nox4 represents a promising therapeutic strategy for AD.
