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1.  Histone Deacetylase 2 in the Mouse Hippocampus: Attenuation of Age-Related Increase by Caloric Restriction 
Current Alzheimer research  2013;10(8):868-876.
The aging process in the hippocampus is associated with aberrant epigenetic marks, such as DNA methylation and histone tail alterations. Recent evidence suggests that caloric restriction (CR) can potentially delay the aging process, while upregulation of antioxidants may also have a beneficial effect in this respect. We have recently observed that CR attenuates age-related changes in the levels of the epigenetic molecules DNA methyltransferase 3a, 5-methylcytidine (5-mC) and 5-hydroxymethylcytosine in the mouse hippocampus while overexpression of the antioxidant Cu/Zn superoxide dismutase 1 (SOD1) does not. However, the impact of aging on the levels of histone-modifying enzymes such as histone deacetylase 2 (HDAC2) in the hippocampus has not been studied in much detail. Here, we investigated immunoreactivity (IR) of HDAC2 in three subregions of the hippocampus (dentate gyrus, CA3 and CA1-2) of mice taken from large cohorts of aging wild-type and transgenic mice overexpressing normal human SOD1, which were kept under normal diet or CR from weaning onwards. Independent from the genotype, aging (between 12 and 24 months) increased levels of HDAC2 IR in the hippocampus. Moreover, CR prevented this age-related increase, particularly in the CA3 and CA1-2 subregions, while SOD1 overexpression did not. Quantitative image analyses showed that HDAC2 IR correlated positively with 5-mC IR while these markers were shown to colocalize in the nucleus of hippocampal cells. Together with recent literature reports, these findings suggest that altered levels of epigenetic regulatory proteins including HDAC2 regulate age-related changes in the mouse hippocampus and that CR may prevent these age-related changes.
PMCID: PMC3966721  PMID: 24093534
Aging; epigenesis; histone deacetylase 2 (HDAC2); caloric restriction; hippocampus
2.  Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients 
Neurobiology of aging  2013;34(9):2091-2099.
Epigenetic dysregulation of gene expression is thought to be critically involved in the pathophysiology of Alzheimer’s disease (AD). Recent studies indicate that DNA methylation and DNA hydroxymethylation are 2 important epigenetic mechanisms that regulate gene expression in the aging brain. However, very little is known about the levels of markers of DNA methylation and hydroxymethylation in the brains of patients with AD, the cell-type specificity of putative AD-related alterations in these markers, as well as the link between epigenetic alterations and the gross pathology of AD. The present quantitative immunohistochemical study investigated the levels of the 2 most important markers of DNA methylation and hydroxymethylation, that is, 5-methylcytidine (5-mC) and 5-hydroxymethylcytidine (5-hmC), in the hippocampus of AD patients (n = 10) and compared these to non demented, age-matched controls (n = 10). In addition, the levels of 5-hmC in the hippocampus of a pair of monozygotic twins discordant for AD were assessed. The levels of 5-mC and 5-hmC were furthermore analyzed in a cell-type and hippocampal subregion–specific manner, and were correlated with amyloid plaque load and neurofibrillary tangle load. The results showed robust decreases in the hippocampal levels of 5-mC and 5-hmC in AD patients (19.6% and 20.2%, respectively). Similar results were obtained for the twin with AD when compared to the non-demented co-twin. Moreover, levels of 5-mC as well as the levels of 5-hmC showed a significant negative correlation with amyloid plaque load in the hippocampus (rp = −0.539, p = 0.021 for 5-mC and rp = −0.558, p = 0.016 for 5-hmC). These human postmortem results thus strengthen the notion that AD is associated with alterations in DNA methylation and hydroxymethylation, and provide a basis for further epigenetic studies identifying the exact genetic loci with aberrant epigenetic signatures.
doi:10.1016/j.neurobiolaging.2013.02.021
PMCID: PMC3955118  PMID: 23582657
Alzheimer’s disease; Epigenetics; DNA methylation; DNA hydroxymethylation; Amyloid
3.  Autoantibodies to neurotransmitter receptors and ion channels: from neuromuscular to neuropsychiatric disorders 
Frontiers in Genetics  2013;4:181.
Changes of voltage-gated ion channels and ligand-gated receptor channels caused by mutation or autoimmune attack are the cause of so-called channelopathies in the central and peripheral nervous system. We present the pathophysiology of channelopathies of the neuromuscular junction in terms of loss-of-function and gain-of-function principles. Autoantibodies generally have reduced access to the central nervous system, but in some cases this is enough to cause disease. A review is provided of recent findings implicating autoantibodies against ligand-activated receptor channels and potassium channels in psychiatric and neurological disorders, including schizophrenia and limbic encephalitis. The emergence of channelopathy-related neuropsychiatric disorders has implications for research and practice.
doi:10.3389/fgene.2013.00181
PMCID: PMC3778371  PMID: 24065983
NMDA receptor; AMPA receptor; GABA receptor; glycine receptor; acetylcholine receptor; Caspr2; Lgi1; potassium channel
4.  Age-related increase in levels of 5-hydroxymethylcytosine in mouse hippocampus is prevented by caloric restriction 
Current Alzheimer research  2012;9(5):536-544.
Aberrations in epigenetic marks have been associated with aging of the brain while caloric restriction (CR) and upregulation of endogenous antioxidants have been suggested as tools to attenuate the aging process. We have recently observed age-related increases in levels of 5-methylcytidine (5-mC) and DNA methyltransferase 3a (Dnmt3a) in the mouse hippocampus. Most of those age-related changes in these epigenetic relevant markers were prevented by CR but not by transgenic overexpression of the endogenous antioxidant superoxide dismutase 1 (SOD1). As recent work has suggested a distinct role for hydroxymethylation in epigenetic regulation of gene expression in the brain, the current study investigated age-related changes of 5-hydroxymethylcytosine (5-hmC) in the mouse hippocampus, and furthermore tested whether CR and transgenic upregulation of SOD1 affected any age-related changes in 5-hmC. Immunohistochemical analyses of 5-hmC in 12- and 24-month-old wild-type and transgenic mice overexpressing SOD1, which were kept under either a control or a calorie restricted diet, revealed an increase of 5-hmC immunoreactivity occurring with aging in the hippocampal dentate gyrus, CA3 and CA1–2 regions. Moreover, CR, but not overexpression of SOD1, prevented the age-related increase in the CA3 region. These region-specific findings indicate that the aging process in mice is connected with epigenetic changes and suggest that the beneficial actions of CR may be mediated via epigenetic mechanisms such as methylation and hydroxymethylation of DNA.
PMCID: PMC3561726  PMID: 22272625
Aging; Epigenesis; Epigenetics; DNA hydroxymethylation; 5-hydroxymethylcytosine; Caloric restriction; Antioxidants; superoxide dismutase (SOD); Hippocampus
5.  Prevention of age-related changes in hippocampal levels of 5-methylcytidine by caloric restriction 
Neurobiology of Aging  2011;33(8):1672-1681.
Aberrant DNA methylation patterns have been linked to molecular and cellular alterations in the aging brain. Caloric restriction (CR) and upregulation of antioxidants have been proposed as interventions to prevent or delay age-related brain pathology. Previously, we have shown in large cohorts of aging mice, that age-related increases in DNA methyltransferase 3a (Dnmt3a) immunoreactivity in the mouse hippocampus were attenuated by CR, but not by overexpression of superoxide dismutase 1 (SOD1). Here, we investigated age-related alterations of 5-methylcytidine (5-mC), a marker of DNA methylation levels, in a hippocampal subregion-specific manner. Examination of 5-mC immunoreactivity in 12- and 24-month-old wild type (WT) mice on control diet, mice overexpressing SOD1 on control diet, wild type mice on CR, and SOD1 mice on CR, indicated an age-related increase in 5-mC immunoreactivity in the hippocampal dentate gyrus, CA3, and CA1–2 regions, which was prevented by CR but not by SOD1 overexpression. Moreover, positive correlations between 5-mC and Dnmt3a immunoreactivity were observed in the CA3 and CA1–2. These findings suggest a crucial role for DNA methylation in hippocampal aging and in the mediation of the beneficial effects of CR on aging.
doi:10.1016/j.neurobiolaging.2011.06.003
PMCID: PMC3355211  PMID: 21764481
Aging; Epigenesis; Epigenetics; DNA methylation; 5-methylcytidine (5-mC); Caloric restriction; Antioxidants; Superoxide dismutase (SOD); Hippocampus
6.  Age-related changes of neuron numbers in the frontal cortex of a transgenic mouse model of Alzheimer’s disease 
Brain Structure & Function  2011;216(3):227-237.
Alzheimer’s disease (AD) is a neurodegenerative disorder, characterized by amyloid plaque accumulation, intracellular tangles and neuronal loss in selective brain regions. The frontal cortex, important for executive functioning, is one of the regions that are affected. Here, we investigated the neurodegenerative effects of mutant human amyloid precursor protein (APP) and presenilin 1 (PS1) on frontal cortex neurons in APP/PS1KI mice, a transgenic mouse model of AD, expressing two mutations in the human APP, as well as two human PS1 mutations knocked-in into the mouse PS1 gene in a homozygous (ho) manner. Although the hippocampus is significantly affected in these mice, very little is known about the effects of these mutations on selective neuronal populations and plaque load in the frontal cortex. In this study, cytoarchitectural changes were characterized using high precision design-based stereology to evaluate plaque load, total neuron numbers, as well as total numbers of parvalbumin- (PV) and calretinin- (CR) immunoreactive (ir) neurons in the frontal cortex of 2- and 10-month-old APP/PS1KI mice. The frontal cortex was divided into two subfields: layers II–IV and layers V–VI, the latter of which showed substantially more extracellular amyloid-beta aggregates. We found a 34% neuron loss in layers V–VI in the frontal cortex of 10-month-old APP/PS1KI mice compared to 2-month-old, while there was no change in PV- and CR-ir neurons in these mice. In addition, the plaque load in layers V–VI of 10-month-old APP/PS1KI mice was only 11% and did not fully account for the extent of neuronal loss. Interestingly, an increase was found in the total number of PV-ir neurons in all frontal cortical layers of single transgenic APP mice and in layers II–IV of single transgenic PS1ho mice between 2 and 10 months of age. In conclusion, the APP/PS1KI mice provide novel insights into the regional selective vulnerability in the frontal cortex during AD that, together with previous findings in the hippocampus, are remarkably similar to the human situation.
doi:10.1007/s00429-011-0305-1
PMCID: PMC3155024  PMID: 21409417
Alzheimer’s disease; Neuropathology; Stereology; Frontal cortex; Mouse model
7.  Epigenetic Mediation of Environmental Influences in Major Psychotic Disorders 
Schizophrenia Bulletin  2009;35(6):1045-1056.
The major psychotic disorders schizophrenia and bipolar disorder are etiologically complex involving both heritable and nonheritable factors. The absence of consistently replicated major genetic effects, together with evidence for lasting changes in gene expression after environmental exposures, is consistent with the concept that the biologic underpinnings of these disorders are epigenetic in form rather than DNA sequence based. Psychosis-associated environmental exposures, particularly at key developmental stages, may result in long-lasting epigenetic alterations that impact on the neurobiological processes involved in pathology. Although direct evidence for epigenetic dysfunction in both schizophrenia and bipolar disorder is still limited, methodological technologies in epigenomic profiling have advanced. This means that we are at the exciting stage where it is feasible to start investigating molecular modifications to DNA and histones and examine the mechanisms by which environmental factors can act upon the genome to bring about epigenetic changes in gene expression involved in the etiology of these disorders. Given the dynamic nature of the epigenetic machinery and potential reversibility of epigenetic modifications, the understanding of such mechanisms is of key relevance for clinical psychiatry and for identifying new targets for prevention and/or intervention.
doi:10.1093/schbul/sbp104
PMCID: PMC2762629  PMID: 19783603
DNA methylation; histone modifications; development; schizophrenia; bipolar disorder; gene-environment interaction
8.  Hippocampal interneuron loss in an APP/PS1 double mutant mouse and in Alzheimer’s disease 
Brain structure & function  2010;214(2-3):145-160.
Hippocampal atrophy and neuron loss are commonly found in Alzheimer’s disease (AD). However, the underlying molecular mechanisms and the fate in the AD hippocampus of subpopulations of interneurons that express the calcium-binding proteins parvalbumin (PV) and calretinin (CR) has not yet been properly assessed. Using quantitative stereologic methods, we analyzed the regional pattern of age-related loss of PV- and CR-immunoreactive (ir) neurons in the hippocampus of mice that carry M233T/L235P knocked-in mutations in presenilin-1 (PS1) and overexpress a mutated human beta-amyloid precursor protein (APP), namely, the APPSL/PS1 KI mice, as well as in APPSL mice and PS1 KI mice. We found a loss of PV-ir neurons (40–50%) in the CA1-2, and a loss of CR-ir neurons (37–52%) in the dentate gyrus and hilus of APPSL/PS1 KI mice. Interestingly, comparable PV- and CR-ir neuron losses were observed in the dentate gyrus of postmortem brain specimens obtained from patients with AD. The loss of these interneurons in AD may have substantial functional repercussions on local inhibitory processes in the hippocampus.
doi:10.1007/s00429-010-0242-4
PMCID: PMC3038332  PMID: 20213270
Alzheimer’s disease; Amyloid precursor protein; Calcium-binding proteins; Hippocampus; Presenilin-1; Stereology

Results 1-8 (8)