Altered Histone 4 K12 Acetylation is Associated with Age Dependent Memory Impairment in Mice

Abstract

The remarkable capability of the nervous system of animals to adapt their behavioral responses to an ever-changing environmental conditions is thought to rely on the plasticity of neuronal circuits and synaptic connections. This capability reaches its highest form in the human brain. During aging, a marked decline is frequently observed in the performance of cognitive and memory tasks that require such plasticity. Age-associated memory loss and memory impairment during neurodegenerative diseases such as Alzheimer s disease (AD) affect millions of people worldwide. No treatment to this day has been successful in restoring these memory deficits. This lack of therapy is primarily due to the fact that little is known about the underlying molecular mechanisms that lead to memory formation. A number of recent studies suggest that epigenetic factors may play a central role in memory formation and age related pathologies. In addition to the role of transcription factors, the availability of genes for transcription is controlled by a series of proteins that regulate epigenetic chromatin remodeling, especially histone-acetyltransferases (HATs) and histone-deacetylases (HDACs). The goal of this research was to further elucidate the molecular and cellular terms of how the aging process modifies the capability of the hippocampus to generate plastic responses and the consequences that epigenetic alterations have in learning and memory in elderly mice.We showed that already at 16 month-old, mice show impaired freezing behaviour in the fear conditioning test. We demonstrate that during the memory consolidation H4K12 acetylation site is uniquely dysregulated in 16 month-old mice when compared with 3 month-old mice. This deficit is linked with failure to up-regulate learning induced gene expression, required for consolidation of associative memory. The deficit in H4K12 acetylation observed in 16 month-old mice is uniquely observed in the gene bodies of the up regulated genes. As such, H4K12 acetylation seems to be of particular importance for transcriptional elongation. We found that the administration of HDAC inhibitors that shift the balance of H4K12 acetylation is able to reinstate learning-induced gene expression and memory function in 16-month-old mice. Our data also suggest that H4K12 acetylation dependent changes in gene expression may serve as an early biomarker for an impaired genome-environment interaction in the aging brain.Finally our novel findings, along with other recent publications, suggest that H4K12 dysregulation may be linked with other age related phenomena due to the special dependence of histone acetylation on metabolism. Thus H4K12 may serve as a general therapeutic target for age related diseases. Future studies will be able to determine the H4K12 acetylation mechanism more in detail and reveal further novel targets to treat age related maladies.