MiR-204-3p/Nox4 Mediates Memory Deficits in a Mouse Model of Alzheimer's Disease

Overview

Journal Mol Ther

Publisher Cell Press

Specialties Molecular Biology
Pharmacology

Date 2020 Sep 20

PMID 32950103

Citations 34

Authors

Wenyuan Tao

Linjie Yu

Shu Shu

Ying Liu

Zi Zhuang

Siyi Xu

Xinyu Bao

Yue Gu

Fang Cai

Weihong Song

Yun Xu

Xiaolei Zhu

Affiliations

Soon will be listed here.

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 Aβ-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.

Citing Articles

miR-32533 Reduces Cognitive Impairment and Amyloid-β Overload by Targeting CREB5-Mediated Signaling Pathways in Alzheimer's Disease.

Zeng L, Cai Z, Liu J, Zhao K, Liang F, Sun T Adv Sci (Weinh). 2025; 12(10):e2409986.

PMID: 39840513 PMC: 11905094. DOI: 10.1002/advs.202409986.

Exosomes and non-coding RNAs: bridging the gap in Alzheimer's pathogenesis and therapeutics.

Chunhui G, Yanqiu Y, Jibing C, Ning L, Fujun L Metab Brain Dis. 2025; 40(1):84.

PMID: 39754674 PMC: 11700052. DOI: 10.1007/s11011-024-01520-7.

Potential Regulatory Role of miR-21 on Alzheimer's Disease by Targeting GSK-3β Signaling.

Ding H Galen Med J. 2024; 12:e3027.

PMID: 39464535 PMC: 11512435. DOI: 10.31661/gmj.v12i0.3027.

Acquired sensorineural hearing loss, oxidative stress, and microRNAs.

Nunez D, Guo R Neural Regen Res. 2024; 20(9):2513-2519.

PMID: 39314173 PMC: 11801280. DOI: 10.4103/NRR.NRR-D-24-00579.

NOX4 exacerbates Parkinson's disease pathology by promoting neuronal ferroptosis and neuroinflammation.

Lin Z, Ying C, Si X, Xue N, Liu Y, Zheng R Neural Regen Res. 2024; 20(7):2038-2052.

PMID: 38993139 PMC: 11691449. DOI: 10.4103/NRR.NRR-D-23-01265.

References

Wang X, Liu D, Huang H, Wang Z, Hou T, Yang X . A Novel MicroRNA-124/PTPN1 Signal Pathway Mediates Synaptic and Memory Deficits in Alzheimer's Disease. Biol Psychiatry. 2017; 83(5):395-405. DOI: 10.1016/j.biopsych.2017.07.023. View

Borchelt D, Thinakaran G, Eckman C, Lee M, Davenport F, Ratovitsky T . Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron. 1996; 17(5):1005-13. DOI: 10.1016/s0896-6273(00)80230-5. View

Seo S, Kim T, Kim D, Min K, Kwon T . NOX4-mediated ROS production induces apoptotic cell death via down-regulation of c-FLIP and Mcl-1 expression in combined treatment with thioridazine and curcumin. Redox Biol. 2017; 13:608-622. PMC: 5554966. DOI: 10.1016/j.redox.2017.07.017. View

Rodriguez-Ortiz C, Prieto G, Martini A, Forner S, Trujillo-Estrada L, LaFerla F . miR-181a negatively modulates synaptic plasticity in hippocampal cultures and its inhibition rescues memory deficits in a mouse model of Alzheimer's disease. Aging Cell. 2020; 19(3):e13118. PMC: 7059142. DOI: 10.1111/acel.13118. View

Kuroda J, Ago T, Nishimura A, Nakamura K, Matsuo R, Wakisaka Y . Nox4 is a major source of superoxide production in human brain pericytes. J Vasc Res. 2015; 51(6):429-38. DOI: 10.1159/000369930. View

Cacace R, Sleegers K, Van Broeckhoven C . Molecular genetics of early-onset Alzheimer's disease revisited. Alzheimers Dement. 2016; 12(6):733-48. DOI: 10.1016/j.jalz.2016.01.012. View

Luo Z, Luo W, Li S, Zhao S, Sho T, Xu X . Reactive oxygen species mediated placental oxidative stress, mitochondrial content, and cell cycle progression through mitogen-activated protein kinases in intrauterine growth restricted pigs. Reprod Biol. 2018; 18(4):422-431. DOI: 10.1016/j.repbio.2018.09.002. View

Casas A, Geuss E, Kleikers P, Mencl S, Herrmann A, Buendia I . NOX4-dependent neuronal autotoxicity and BBB breakdown explain the superior sensitivity of the brain to ischemic damage. Proc Natl Acad Sci U S A. 2017; 114(46):12315-12320. PMC: 5699031. DOI: 10.1073/pnas.1705034114. View

Sagy-Bross C, Hadad N, Levy R . Cytosolic phospholipase A2α upregulation mediates apoptotic neuronal death induced by aggregated amyloid-β peptide1-42. Neurochem Int. 2013; 63(6):541-50. DOI: 10.1016/j.neuint.2013.09.007. View

10.

Chen J, Shu S, Chen Y, Liu Z, Yu L, Yang L . AIM2 deletion promotes neuroplasticity and spatial memory of mice. Brain Res Bull. 2019; 152:85-94. DOI: 10.1016/j.brainresbull.2019.07.011. View

11.

Oguchi T, Ono R, Tsuji M, Shozawa H, Somei M, Inagaki M . Cilostazol Suppresses Aβ-induced Neurotoxicity in SH-SY5Y Cells through Inhibition of Oxidative Stress and MAPK Signaling Pathway. Front Aging Neurosci. 2017; 9:337. PMC: 5651005. DOI: 10.3389/fnagi.2017.00337. View

12.

Butterfield D, Reed T, Newman S, Sultana R . Roles of amyloid beta-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment. Free Radic Biol Med. 2007; 43(5):658-77. PMC: 2031860. DOI: 10.1016/j.freeradbiomed.2007.05.037. View

13.

Vilardo E, Barbato C, Ciotti M, Cogoni C, Ruberti F . MicroRNA-101 regulates amyloid precursor protein expression in hippocampal neurons. J Biol Chem. 2010; 285(24):18344-51. PMC: 2881760. DOI: 10.1074/jbc.M110.112664. View

14.

Ma M, Wang J, Zhang Q, Wang R, Dhandapani K, Vadlamudi R . NADPH oxidase in brain injury and neurodegenerative disorders. Mol Neurodegener. 2017; 12(1):7. PMC: 5240251. DOI: 10.1186/s13024-017-0150-7. View

15.

Ma M, Wang J, Dhandapani K, Brann D . Deletion of NADPH oxidase 4 reduces severity of traumatic brain injury. Free Radic Biol Med. 2018; 117:66-75. DOI: 10.1016/j.freeradbiomed.2018.01.031. View

16.

Zhang Y, Song W . Islet amyloid polypeptide: Another key molecule in Alzheimer's pathogenesis?. Prog Neurobiol. 2017; 153:100-120. DOI: 10.1016/j.pneurobio.2017.03.001. View

17.

Zhang S, Cai F, Wu Y, Bozorgmehr T, Wang Z, Zhang S . A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol Psychiatry. 2018; 25(3):603-613. DOI: 10.1038/s41380-018-0101-x. View

18.

Schneider R, McKeever P, Kim T, Graff C, Van Swieten J, Karydas A . Downregulation of exosomal miR-204-5p and miR-632 as a biomarker for FTD: a GENFI study. J Neurol Neurosurg Psychiatry. 2018; 89(8):851-858. PMC: 6045452. DOI: 10.1136/jnnp-2017-317492. View

19.

Selkoe D, Hardy J . The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol Med. 2016; 8(6):595-608. PMC: 4888851. DOI: 10.15252/emmm.201606210. View

20.

Alibhai J, Diack A, Manson J . Unravelling the glial response in the pathogenesis of Alzheimer's disease. FASEB J. 2018; 32(11):5766-5777. DOI: 10.1096/fj.201801360R. View