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Updated: Aug 6, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Epigenetic modification of PKMζ rescues aging-related cognitive impairment
Chen Chen1,2, Shi-Qiu Meng1,2, Yan-Xue Xue2
1Institute of Mental Health, Peking University Sixth Hospital, and Key Laboratory of Mental Health, Beijing 100191, China.
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.
Insights
Aging impairs cognition due to changes in protein kinase Mζ (PKMζ) DNA methylation. Restoring PKMζ levels in the brain
Area of Science:
- Neuroscience
- Molecular Biology
- Aging Research
Background:
- Cognitive decline is a common consequence of aging.
- The molecular mechanisms driving age-related cognitive impairment remain largely unknown.
- Protein kinase Mζ (PKMζ) plays a vital role in maintaining long-term memory.
Purpose of the Study:
- To investigate the role of DNA methylation of PKMζ in the prelimbic cortex (PrL) in age-related cognitive decline.
- To explore PKMζ as a potential therapeutic target for improving cognitive function in aged individuals.
Main Methods:
- Behavioral testing (e.g., fear conditioning, memory retention tests) in young, adult, and aged rats.
- Analysis of DNA methylation patterns of PKMζ in the PrL.
- Assessment of PKMζ protein levels and GluR2 membrane expression.
- Intervention studies involving PKMζ overexpression and environmental enrichment.
Main Results:
- Aged rats exhibited significant cognitive impairment in memory retention.
- Cognitive decline correlated with altered DNA methylation of PKMζ in the PrL.
- Overexpression of PKMζ rescued cognitive deficits in aged rats.
- Environmental enrichment reversed PKMζ hypermethylation and improved cognitive performance in aged rats.
Conclusions:
- Changes in PKMζ DNA methylation in the PrL are linked to aging-associated cognitive impairment.
- PKMζ represents a promising therapeutic target for mitigating age-related cognitive decline.
- Environmental enrichment can positively modulate PKMζ methylation and cognitive function in aging.
