An epigenetic hypothesis of aging-related cognitive dysfunction

Abstract

This brief review will focus on a new hypothesis for the role of epigenetic mechanisms in aging-related disruptions of synaptic plasticity and memory. Epigenetics refers to a set of potentially self-perpetuating, covalent modifications of DNA and post-translational modifications of nuclear proteins that produce lasting alterations in chromatin structure. These mechanisms, in turn, result in alterations in specific patterns of gene expression. Aging-related memory decline is manifest prominently in declarative/episodic memory and working memory, memory modalities anatomically based largely in the hippocampus and prefrontal cortex, respectively. The neurobiological underpinnings of age-related memory deficits include aberrant changes in gene transcription that ultimately affect the ability of the aged brain to be “plastic”. The molecular mechanisms underlying these changes in gene transcription are not currently known, but recent work points toward a potential novel mechanism, dysregulation of epigenetic mechanisms. This has led us to hypothesize that dysregulation of epigenetic control mechanisms and aberrant epigenetic “marks” drive aging-related cognitive dysfunction. Here we focus on this theme, reviewing current knowledge concerning epigenetic molecular mechanisms, as well as recent results suggesting disruption of plasticity and memory formation during aging. Finally, several open questions will be discussed that we believe will fuel experimental discovery.

Sustained Transcription of the Immediate Early GeneArcin the Dentate Gyrus after Spatial Exploration

“…This sparse code may be due to particular features of DG neurons such as the high levels of depolarization before action potential threshold is reached (Barnes and McNaughton, 1980), a different transcriptional repression profile (Penner et al, 2010), and perhaps the number of spikes elicited to a given behavior (Leutgeb et al, 2007). This sparse code theoretically allows the DG to store a large amount of nonoverlapping information, but the code in the DG tends to use the same neurons for several different representations .…”

Epigenetic Regulation of Gene Expression in Physiological and Pathological Brain Processes

“…The aged brain differs drastically from its adult counterpart in terms of gene expression programs (204), which are thought to contribute to age-associated memory impairments (269). Recently, two studies have shown that age-related epigenetic differences might account for cognitive decline during aging.…”

Epigenetic Treatments for Cognitive Impairments

“…For example, Rubenstein-Taybi syndrome, a disorder characterized by numerous physical defects and behavioral deficits, is caused by mutations in the gene for CBP (Petrij et al, 1995). Moreover, the results discussed above indicate that HDAC inhibitors enhance memory formation and could therefore potentially form the basis of pharmacotherapies for disorders of learning and memory, including age-associated cognitive decline and Alzheimer's disease (Abel and Zukin, 2008;Chuang et al, 2009;Penner et al, 2010a). Although this latter possibility is only beginning to be explored in human patients, the validity of this idea has already been confirmed in animal models.…”