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S.11.01 Epigenetics in ageing and Alzheimer's disease
S.11. Epigenetics: challenging new findings in psychiatry efficacy of five antipsychotic drugs (haloperidol, amisulpride, olanzapine, quetiapine and ziprasidone) over one year. Baseline frequency of extrapyramidal symptoms (EPS) in this group of patients was as follows: parkinsonism 11%, akathisia 10%, dystonia 2%, and dyskinesia 1%. The intensity of EPS at baseline was similar in patients antipsychotic-na¨ıve and in those with only a brief prior exposure to antipsychotics (2 weeks), positively correlated with the intensity of negative symptoms and negatively with depressive ones. The increase of parkinsonism symptoms after three months of treatment was highest in patients receiving haloperidol (+13%), and that of akathisia in patients treated with ziprasidone (+14%). After one year, in patients remaining in treatment, both parkinsonism and akathisia symptoms were low: the frequency of parkinsonism was 3%, that of akathisia − 3%, and 4% of patients were taking anticholinergic drugs. Baseline prevalence of metabolic syndrome in EUFEST patients was 5.9%, similar as in general age-matched population, however, 58.5% of subjects had one or more elevated metabolic risks. Increased triglycerides and increased blood pressure were more frequent in men while increased waist circumference and decreased HCL cholesterol − in women. Weight increase during treatment was highest on olanzapine (14 kg) and lowest on ziprasidone (5 kg). The results may suggest that in first-episode schizophrenic patients during the first year of antipsychotic treatment, neither EPS nor metabolic symptoms present significant problems. Disclosure statement: Janusz K. Rybakowski has acted as a consultant or as a speaker for the following companies: Adamed-Poland, AstraZeneca, Bristol-Myers-Squibb, Eli Lilly, Janssen-Cilag, Lundbeck, Sanofi-Aventis and Servier.
S.11. Epigenetics: challenging new findings in psychiatry S.11.01 Epigenetics in ageing and Alzheimer’s disease D. Van den Hove1 ° , L. Chouliaras1 , D. Mastroeni2 , P.D. Coleman2 , K.P. Lesch1 , H.W. Steinbusch1 , B.P. Rutten1 1 Maastricht University, School for Mental Health and Neuroscience Department of Translational Neuroscience, Maastricht, The Netherlands; 2 Banner Sun Health Research Institute, LJ Roberts Center for Alzheimer’s Research, Sun City AZ, USA With the aging of the population, the growing incidence and prevalence of Alzheimer’s disease (AD) increases the burden on individuals and society as a whole. To date, the pathophysiology of AD is not yet fully understood. Recent studies have suggested that epigenetic mechanisms such as DNA methylation and histone modifications may play a pivotal role in its pathogenesis [1]. We have recently observed age-related increases in levels of DNA methyltransferase 3a (Dnmt3a), 5-methylcytidine (5-mC), 5-hydroxymethylcytosine (5-hmC), and histone deacetylase 2 (HDAC2) in the mouse hippocampus (e.g. [2]). Most of those age-related changes in these epigenetically relevant markers were prevented by caloric restriction (CR), but not by transgenic overexpression of the endogenous antioxidant superoxide dismutase 1 (SOD1). Moreover, these age-related epigenetic changes were markedly different in transgenic APPswe/PS1dE9 versus wild-type mice. More recent translational studies by our group on e.g. the human hippocampus support the notion that epigenetic regulation is profoundly disturbed in AD subjects (e.g. [3]). Altogether, these
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findings indicate that aging and AD are associated with epigenetic dysregulation at various levels. Conversely, it is still not fully clear whether the observed epigenetic changes actually represent a cause or a consequence of the disease. Evidently, more research is needed in order to clarify the exact role of epigenetic regulation in the development and course of AD. Research on earlier stages of the disease could provide more insight into its underlying pathophysiology, possibly contributing to the establishment of early diagnosis and the development of more effective treatment strategies. References [1] Chouliaras L, Rutten BP, Kenis G, Peerbooms O, Visser PJ, Verhey F, van Os J, Steinbusch HW, Van den Hove DLA. 2010. Epigenetic regulation in the pathophysiology of Alzheimer’s disease. Prog Neurobiol 90(4): 498–510. [2] Chouliaras L, Van den Hove DLA, Kenis G, Keitel S, Hof PR, van Os J, Steinbusch HW, Schmitz C, Rutten BP. 2012. Prevention of agerelated changes in hippocampal levels of 5-methylcytidine by caloric restriction. Neurobiol Aging 33(8): 1672−81. [3] Chouliaras L, Mastroeni D, Delvaux E, Grover A, Kenis G, Hof PR, Steinbusch HWM, Coleman PD, Rutten BPF, Van den Hove DLA. 2013. Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients. Neurobiol Aging. In Press.
S.11.02 Epigenetic control of stress-induced gene transcription and behaviour: relevance to PTSD J.M.H.M. Reul1 ° 1 University of Bristol, Neuro-Epigenetics Research Group, Bristol, United Kingdom Adaptation to stressful events requires coordinated molecular, physiological and behavioural responses in limbic regions such as the hippocampus. It is thought that aberrant responses to stress in conjunction with genetic vulnerabilities are involved in the development of anxiety-related diseases such as post-traumatic stress disorder (PTSD). Glucocorticoid hormones play a central role in the stress response. Not surprisingly, glucocorticoid function is disturbed in stress-related disorders. Glucocorticoid hormones secreted as a result of a stressful event facilitate the consolidation of memories associated with the stressful event but until recently the underlying molecular mechanisms were unknown. We discovered that in hippocampal neurons stress (forced swimming or novelty)-induced glucocorticoids via glucocorticoid receptors (GRs) facilitate ERK MAPK signalling to downstream chromatin-modifying enzymes resulting in phosphorylation of serine10 and acetylation of lysine14 at histone H3 (H3S10p-K14ac) and leading to induction of the immediate early genes (IEG) c-Fos and Egr-1 [1]. Recent preliminary chromatin immuno-precipitation and sequencing (ChIPseq) studies identified additional neuroplasticity-linked genes associated with the H3S10p-K14ac epigenetic mark. Importantly, the anxiety status plays a modulatory role through the GABAergic system. We reported that the anxiolytic benzodiazepine lorazepam strongly inhibits novelty-evoked signalling, epigenetic and IEG responses whereas the anxiogenic partial inverse GABA-A agonist FG7142 results in hyper-responses to stress [2]. Voluntary exercise, which is anxiolytic and enhances GABA synthesis [3], dampened the molecular responses to stress. Thus, epigenetic control of stress-induced gene transcription responses in hippocampal neurons is regulated by GABAergic mechanisms which may be of relevance to the aetiology of PTSD.
S.11. Epigenetics: challenging new findings in psychiatry S.11.01 Epigenetics in ageing and Alzheimer’s disease D. Van den Hove1 ° , L. Chouliaras1 , D. Mastroeni2 , P.D. Coleman2 , K.P. Lesch1 , H.W. Steinbusch1 , B.P. Rutten1 1 Maastricht University, School for Mental Health and Neuroscience Department of Translational Neuroscience, Maastricht, The Netherlands; 2 Banner Sun Health Research Institute, LJ Roberts Center for Alzheimer’s Research, Sun City AZ, USA With the aging of the population, the growing incidence and prevalence of Alzheimer’s disease (AD) increases the burden on individuals and society as a whole. To date, the pathophysiology of AD is not yet fully understood. Recent studies have suggested that epigenetic mechanisms such as DNA methylation and histone modifications may play a pivotal role in its pathogenesis [1]. We have recently observed age-related increases in levels of DNA methyltransferase 3a (Dnmt3a), 5-methylcytidine (5-mC), 5-hydroxymethylcytosine (5-hmC), and histone deacetylase 2 (HDAC2) in the mouse hippocampus (e.g. [2]). Most of those age-related changes in these epigenetically relevant markers were prevented by caloric restriction (CR), but not by transgenic overexpression of the endogenous antioxidant superoxide dismutase 1 (SOD1). Moreover, these age-related epigenetic changes were markedly different in transgenic APPswe/PS1dE9 versus wild-type mice. More recent translational studies by our group on e.g. the human hippocampus support the notion that epigenetic regulation is profoundly disturbed in AD subjects (e.g. [3]). Altogether, these
S127
findings indicate that aging and AD are associated with epigenetic dysregulation at various levels. Conversely, it is still not fully clear whether the observed epigenetic changes actually represent a cause or a consequence of the disease. Evidently, more research is needed in order to clarify the exact role of epigenetic regulation in the development and course of AD. Research on earlier stages of the disease could provide more insight into its underlying pathophysiology, possibly contributing to the establishment of early diagnosis and the development of more effective treatment strategies. References [1] Chouliaras L, Rutten BP, Kenis G, Peerbooms O, Visser PJ, Verhey F, van Os J, Steinbusch HW, Van den Hove DLA. 2010. Epigenetic regulation in the pathophysiology of Alzheimer’s disease. Prog Neurobiol 90(4): 498–510. [2] Chouliaras L, Van den Hove DLA, Kenis G, Keitel S, Hof PR, van Os J, Steinbusch HW, Schmitz C, Rutten BP. 2012. Prevention of agerelated changes in hippocampal levels of 5-methylcytidine by caloric restriction. Neurobiol Aging 33(8): 1672−81. [3] Chouliaras L, Mastroeni D, Delvaux E, Grover A, Kenis G, Hof PR, Steinbusch HWM, Coleman PD, Rutten BPF, Van den Hove DLA. 2013. Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients. Neurobiol Aging. In Press.
S.11.02 Epigenetic control of stress-induced gene transcription and behaviour: relevance to PTSD J.M.H.M. Reul1 ° 1 University of Bristol, Neuro-Epigenetics Research Group, Bristol, United Kingdom Adaptation to stressful events requires coordinated molecular, physiological and behavioural responses in limbic regions such as the hippocampus. It is thought that aberrant responses to stress in conjunction with genetic vulnerabilities are involved in the development of anxiety-related diseases such as post-traumatic stress disorder (PTSD). Glucocorticoid hormones play a central role in the stress response. Not surprisingly, glucocorticoid function is disturbed in stress-related disorders. Glucocorticoid hormones secreted as a result of a stressful event facilitate the consolidation of memories associated with the stressful event but until recently the underlying molecular mechanisms were unknown. We discovered that in hippocampal neurons stress (forced swimming or novelty)-induced glucocorticoids via glucocorticoid receptors (GRs) facilitate ERK MAPK signalling to downstream chromatin-modifying enzymes resulting in phosphorylation of serine10 and acetylation of lysine14 at histone H3 (H3S10p-K14ac) and leading to induction of the immediate early genes (IEG) c-Fos and Egr-1 [1]. Recent preliminary chromatin immuno-precipitation and sequencing (ChIPseq) studies identified additional neuroplasticity-linked genes associated with the H3S10p-K14ac epigenetic mark. Importantly, the anxiety status plays a modulatory role through the GABAergic system. We reported that the anxiolytic benzodiazepine lorazepam strongly inhibits novelty-evoked signalling, epigenetic and IEG responses whereas the anxiogenic partial inverse GABA-A agonist FG7142 results in hyper-responses to stress [2]. Voluntary exercise, which is anxiolytic and enhances GABA synthesis [3], dampened the molecular responses to stress. Thus, epigenetic control of stress-induced gene transcription responses in hippocampal neurons is regulated by GABAergic mechanisms which may be of relevance to the aetiology of PTSD.