Age-related cognitive decline is considered to be a consequence of the normal aging process in healthy adults and can result in slight impairments in working memory and other functional tasks. However, in neurodegenerative disease states such as Alzheimer disease, dementia severely impairs one’s memory, intellectual and social abilities, and causes a loss of identity. While a full understanding of the cellular and molecular processes in age-related cognitive decline or dementia is still lacking, a growing body of evidence suggests that epigenetic regulation and dysfunction of specific genes may play a central role in the pathogenesis of neurological disorders (for review, see Roth and Sweatt, 2009).

In the epigenetic landscape, various modifications, including histone acetylation or deacetylation, serve as important markers for chromatin remodeling and subsequently gene transcription. Histone deacetylase inhibitors (HDACi’s) allow for increased gene transcription by preventing the removal of the acetyl group on a lysine residue on a histone. HDACi’s have potential...  Read more

Age-related cognitive decline is considered to be a consequence of the normal aging process in healthy adults and can result in slight impairments in working memory and other functional tasks. However, in neurodegenerative disease states such as Alzheimer disease, dementia severely impairs one’s memory, intellectual and social abilities, and causes a loss of identity. While a full understanding of the cellular and molecular processes in age-related cognitive decline or dementia is still lacking, a growing body of evidence suggests that epigenetic regulation and dysfunction of specific genes may play a central role in the pathogenesis of neurological disorders (for review, see Roth and Sweatt, 2009).

In the epigenetic landscape, various modifications, including histone acetylation or deacetylation, serve as important markers for chromatin remodeling and subsequently gene transcription. Histone deacetylase inhibitors (HDACi’s) allow for increased gene transcription by preventing the removal of the acetyl group on a lysine residue on a histone. HDACi’s have potential therapeutic applications for mouse models of Huntington disease (Hockly et al., 2003), Rubinstein-Taybi syndrome (Alarcon et al., 2004), and most recently, Alzheimer disease (Fischer et al., 2007; Guan et al., 2009).

Now, for the first time, Fischer and colleagues have undertaken in this paper a comprehensive approach to screening epigenetic changes in normal aging mice. They examined various epigenetic modifications in different groups of mice and found only one residue, histone 4 lysine 12 (H4K12) acetylation, to be decreased in older mice. Moreover, these aged mice display impaired memory formation as measured by hippocampus-dependent contextual fear conditioning as well as spatial learning as shown by the Morris water maze tasks. These impairments were not due to alterations in neuronal morphology or differences in sensory components that would affect the task at hand.

To further explore the underlying mechanisms for their observations, the authors performed an oligonucleotide microarray to determine if there are specific genes that are altered. They found no changes in HDAC activity; however, they noticed that there was a category of genes that they termed “learning-regulated genes” that are not properly regulated in older mice. Furthermore, ChIP-sequencing technology allowed the authors to probe which part of DNA exhibited altered H4K12 acetylation in aged mice. To this end, they found that the genomic region downstream of the transcription start site had impaired H4K12 acetylation and concluded that there is an impairment of transcriptional elongation. As proof of concept, the gene Formin 2 (Fmn2) is found to lack H4K12 acetylation in older mice. The Fmn2 knockout mice also display age-associated memory formation. Strikingly, this impairment was reversed after hippocampal SAHA (an HDACi) treatment, which, in turn, increased H4K12 acetylation, consistent with earlier observations.

The paper compellingly demonstrates that a particular epigenetic marker, in this case H4K12 acetylation, is altered in age-related cognitive decline and leads to altered gene expression. Future studies will undoubtedly focus on the mechanisms that target H4K12 acetylation and the detection of other epigenetic changes that may be involved during the aging process. Nevertheless, this study is the first to address a key alteration in the epigenetic landscape that is specific to aging and occurs before any visible neuronal loss. It also highlights the intriguing concept of developing therapies that can potentially reverse dysregulated epigenetic markers during neurodegenerative states and restore memory.

References:
Roth TL, Sweatt JD. Regulation of chromatin structure in memory formation. Curr Opin Neurobiol. 2009;19:336-342. Abstract

Hockly E, Richon VM, Woodman B, Smith DL, Zhou X, Rosa E, Sathasivam K, Ghazi-Noori S, Mahal A, Lowden PA, Steffan JS, Marsh JL, Thompson LM, Lewis CM, Marks PA, Bates GP. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc Natl Acad Sci U S A. 2003;100:2041-2046. Abstract

Alarcón, JM, Malleret G, Touzani K, Vronskaya S, Ishii S, Kandel ER and Barco A. Chromatin acetylation, memory, and LTP are impaired in CBP+/- Mice: A model for the cognitive deficit in Rubinstein-Taybi Syndrome and its amelioration. 2004 Neuron 2004;42:947-959. Abstract

Fischer A, Sananbenesi F, Wang X, Dobbin M, Tsai LH. Recovery of learning and memory is associated with chromatin remodelling. Nature 2007;447(7141):178-82. Abstract

Guan JS, Haggarty SJ, Giacometti E, Dannenberg JH, Joseph N, Gao J, Nieland TJ, Zhou Y, Wang X, Mazitschek R, Bradner JE, DePinho RA, Jaenisch R, Tsai LH. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 2009;459:55-60. Abstract

View all comments by Susan Su
View all comments by Li-Huei Tsai

This article identifies altered histone acetylation as an early biomarker of memory impairment. More specifically, the authors show an altered acetylation response of a specific lysine residue, i.e., K12, of histone 4 in older mice, but not in young mice. Notably, age-dependent changes in K12 acetylation on H4 were ameliorated in mice treated with the drug SAHA, a pan-inhibitor of histone deacetylases. HDAC inhibitors may therefore provide a feasible approach for treating memory loss in human neurodegenerative conditions like Alzheimer disease. In that respect, future studies will have to demonstrate memory improvement in Alzheimer disease animal models treated with HDAC inhibitors, and correlate efficacy with changes in the acetylation state of H4K12. If these studies are positive, developing HDAC-based therapeutics appears feasible for symptomatic treatment of AD. However, while these results provide optimism, I would recommend caution at this stage, because results achieved in early pre-clinical studies often do not translate into efficacious effects in human trials.

View all comments by Aleksey Kazantsev