Dysfunction of striatal MeCP2 is associated with cognitive decline in a mouse model of Alzheimer's disease.

Rationale: Cerebral Methyl-CpG binding Protein 2 (MeCP2) is involved in several psychiatric disorders that are concomitant with cognitive dysfunction. However, the regulatory function of striatal MeCP2 and its association with Alzheimer's disease (AD) has been largely neglected due to the absence of amyloid plaque accumulation in the striatal region until the later stages of AD progression. Considerable evidence indicates that neuropsychiatric symptoms related to cognitive decline are involved with striatal dysfunction. To this respect, we investigated the epigenetic function of striatal MeCP2 paralleling the pathogenesis of AD. Methods: We investigated the brain from amyloid precursor protein (APP)/presenilin1 (PS1) transgenic mice and postmortem brain samples from normal subjects and AD patients. The molecular changes in the brain, particularly in the striatal regions, were analyzed with thioflavin S staining, immunohistochemistry, immunoblotting, and MeCP2 chromatin immunoprecipitation sequencing (ChIP-seq). The cognitive function of APP/PS1 mice was assessed via three behavioral tests: 3-chamber test (3CT), Y-maze test (YMT), and passive avoidance test (PA). A multi-electrode array (MEA) was performed to analyze the neuronal activity of the striatum in APP/PS1 mice. Results: Striatal MeCP2 expression was increased in the younger (6 months) and older (10 months) ages of APP/PS1 mice, and the genome-wide occupancy of MeCP2 in the younger APP/PS1 showed dysregulated binding patterns in the striatum. Additionally, we confirmed that APP/PS1 mice showed behavioral deficits in multiple cognitive behaviors. Notably, defective cognitive phenotypes and abnormal neuronal activity in old APP/PS1 mice were rescued through the knock-down of striatal MeCP2. Conclusion: We found that the MeCP2-mediated dysregulation of the epigenome in the striatum is linked to the defects in cognitive behavior and neuronal activity in the AD animal model, and that this alteration is initiated even in the very early stages of AD pathogenesis. Together, our data indicates that MeCP2 may be a potential target for the diagnosis and treatment of AD at asymptomatic and symptomatic stages.

Age-Related Decrease in Stress Responsiveness and Proactive Coping in Male Mice.

Coping is a strategic approach to dealing with stressful situations. Those who use proactive coping strategies tend to accept changes and act before changes are expected. In contrast, those who use reactive coping are less flexible and more likely to act in response to changes. However, little research has assessed how coping style changes with age. This study investigated age-related changes in coping strategies and stress responsiveness and the influence of age on the processing of conditioned fear memory in 2-, 12- and 23-month-old male mice. Coping strategy was measured by comparing the escape latency in an active avoidance test and by comparing responses to a shock prod. The results showed that proactivity in coping response gradually decreased with age. Stress responsiveness, measured by stress-induced concentration of corticosterone, was also highest in 2-month-old mice and decreased with age. Consolidation of fear memory was highest in 12-month-old mice and was negatively correlated with the degree of stress responsiveness and proactivity in coping. Fear extinction did not differ among age groups and was not correlated with stress responsiveness or the proactivity of coping. However, the maintenance of extinct fear memory, which was best in 2-month-old mice and worst in 12-month-old mice, was negatively correlated with stress responsiveness but not with coping style. Age-dependent changes in the expression of glucocorticoid receptor (GR) and its regulatory co-chaperones, which are accepted mechanisms for stress hormone stimulation, were measured in the hippocampus. The expression of GR was increased at 12 months compared to other age groups. There were no differences in Hsp70 and BAG1 expression by age. These results can be summarized as follows: (1) stress responsiveness and proactivity in coping decreased with age class; (2) consolidation of fear memory was negatively correlated with both stress responsiveness and proactivity; however, maintenance of extinct fear memory was negatively correlated with stress responsiveness only; and (3) consolidation and maintenance of extinct fear memory appeared to be more influenced by factors other than stress reactivity and proactivity in coping, such as the amount of hippocampal glucocorticoid expression.