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

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. [Display omitted] Zhu and colleagues demonstrate that miR-204-3p attenuates memory and synaptic deficits in APPswe/PS1dE9 (APP/PS1) mice via inhibition of NADPH oxidase 4 (Nox4). In addition, Nox4 inhibition by GLX351322 rescues memory deficits in APP/PS1 mice, suggesting that miR-204-3p overexpression and/or Nox4 inhibition is a potential therapeutic strategy for Alzheimer’s disease treatment.