Epigenetic modification of PKMζ rescues aging-related cognitive impairment.

Chen Chen,Wei-Hong Song,Jie Shi,Yan-Xue Xue,Lin-Lin Cao,Yan-Ping Bao,Shi-Qiu Meng,Jia-Hui Deng,Fei-Long Zhang,Cheng-Yu Sun,Ying Han,Wei-Guo Zhu,Lin Lu,Na Chen

doi:10.1038/srep22096

Abstract

Cognition is impacted by aging. However, the mechanisms that underlie aging-associated cognitive impairment are unclear. Here we showed that cognitive decline in aged rats was associated with changes in DNA methylation of protein kinase Mζ (PKMζ) in the prelimbic cortex (PrL). PKMζ is a crucial molecule involved in the maintenance of long-term memory. Using different behavioral models, we confirmed that aged rats exhibited cognitive impairment in memory retention test 24 h after training, and overexpression of PKMζ in the PrL rescued cognitive impairment in aged rats. After fear conditioning, the protein levels of PKMζ and the membrane expression of GluR2 increased in the PrL in young and adult rats but not in aged rats, and the levels of methylated PKMζ DNA in the PrL decreased in all age groups, whereas the levels of unmethylated PKMζ DNA increased only in young and adult rats. We also found that environmentally enriched housing reversed the hypermethylation of PKMζ and restored cognitive performance in aged rats. Inactivation of PKMζ prevented the potentiating effects of environmental enrichment on memory retention in aged rats. These results indicated that PKMζ might be a potential target for the treatment of aging-related cognitive impairment, suggesting a potential therapeutic avenue.

Highlights

Cognitive functions, especially those that involve the medial prefrontal cortex, decline with age, and the most notable manifestation is impaired memory[1,2,3]
We found that aged rats exhibited normal short-term memory (STM) but displayed decreased freezing time in long-term memory (LTM)
In the Morris water maze (MWM) and novel object recognition (NOR) test, we found that LTM was impaired in aged rats (Fig. 1C–I)

Summary

Introduction

Especially those that involve the medial prefrontal cortex (mPFC), decline with age, and the most notable manifestation is impaired memory[1,2,3]. Reduced expression of neural cell adhesion molecule in the hippocampus and mPFC might be a critical factor for aging-related cognitive impairments in MWM and T-maze[11]. Aberrant changes in methylation of the Arc gene contribute to aging-related decreases in Arc transcription within the Cornu Ammonis 1 (CA1) area and dentate gyrus of the hippocampus, leading to impairment in spatial memory[15]. In the past few years, PKMζ in multiple brain areas, such as the hippocampus[19], mPFC20,21, amygdala[22] and neocortex[23], has been identified as a crucial molecule in the maintenance of long-term spatial[24], instrumental[25] and emotional memories[23]. We explored whether the aberrant methylation of PKMζ DNA in the prelimbic cortex (PrL) is involved in aging-related memory decline and whether cognitive impairment in aged rats can be rescued through regulation of PKMζ

Methods

Results

Conclusion