A phage displaying an Aβ-interacting peptide mitigates neurotoxicity and prevents Aβ-driven gene expression changes

A Cellular Memory of Developmental History Generates Phenotypic Diversity in C. elegans

Editor's evaluation: Comparative transcriptomic analysis reveals translationally relevant processes in mouse models of malaria

Differentiated pancreatic beta cells are unique in their ability to secrete insulin in response to a rise in plasma glucose. We have proposed that the unique constellation of genes they express may be lost in diabetes due to the deleterious effect of chronic hyperglycemia. To test this hypothesis, Sprague-Dawley rats were submitted to a 85-95% pancreatectomy or sham pancreatectomy. One week later, the animals developed mild to severe chronic hyperglycemia that was stable for the next 3 weeks, without significant alteration of plasma nonesterified fatty acid levels. Expression of many genes important for glucose-induced insulin release decreased progressively with increasing hyperglycemia, in parallel with a reduction of several islet transcription factors involved in beta cell development and differentiation. In contrast, genes barely expressed in sham islets (lactate dehydrogenase A and hexokinase I) were markedly increased, in parallel with an increase in the transcription factor c-Myc, a potent stimulator of cell growth. These abnormalities were accompanied by beta cell hypertrophy. Changes in gene expression were fully developed 2 weeks after pancreatectomy. Correction of blood glucose by phlorizin for the next 2 weeks normalized islet gene expression and beta cell volume without affecting plasma nonesterified fatty acid levels, strongly suggesting that hyperglycemia triggers these abnormalities. In conclusion, chronic hyperglycemia leads to beta cell hypertrophy and loss of beta cell differentiation that is correlated with changes in c-Myc and other key transcription factors. A similar change in beta cell differentiation could contribute to the profound derangement of insulin secretion in human diabetes.

The amnesic potential of scopolamine is well manifested through synaptic plasticity gene expression changes and behavioral paradigms of memory impairment. However, the underlying mechanism remains obscure and consequently ideal therapeutic target is lacking. In this context, chromatin-modifying enzymes, which regulate memory gene expression changes, deserve major attention. Therefore, we analyzed the expression of chromatin-modifying enzymes and recovery potential of enzyme modulators in scopolamine-induced amnesia. Scopolamine administration drastically up-regulated DNA methyltransferases (DNMT1) and HDAC2 expression while CREB-binding protein (CBP), DNMT3a and DNMT3b remained unaffected. HDAC inhibitor sodium butyrate and DNMT inhibitor Aza-2'deoxycytidine recovered scopolamine-impaired hippocampal-dependent memory consolidation with concomitant increase in the expression of synaptic plasticity genes Brain-derived neurotrophic factor (BDNF) and Arc and level of histone H3K9 and H3K14 acetylation and decrease in DNA methylation level. Sodium butyrate showed more pronounced effect than Aza-2'deoxycytidine and their co-administration did not exhibit synergistic effect on gene expression. Taken together, we showed for the first time that scopolamine-induced up-regulation of chromatin-modifying enzymes, HDAC2 and DNMT1, leads to gene expression changes and consequent decline in memory consolidation. Our findings on the action of scopolamine as an epigenetic modulator can pave a path for ideal therapeutic targets. We propose the following putative pathway for scopolamine-mediated memory impairment; scopolamine up-regulates hippocampal DNMT1 and HDAC2 expression, induces methylation and deacetylation of BDNF and Arc promoter, represses gene expression and eventually impairs memory consolidation. On the other hand, Aza-2 and NaB inhibit DNMT1 and HDAC2 respectively, up-regulate BDNF and Arc expression and recover memory consolidation. We elucidate the action of scopolamine as an epigenetic modulator and hope that DNMT1 and HDAC2 would be ideal therapeutic targets for memory disorders.

Gene profiling methods have been widely useful for delineating changes in gene expression as an approach for gaining insight into the mechanism of rejection or disease pathology. Herein, we use gene profiling to compare changes in gene expression associated with different orthotopic cardiac xenotransplantation (OCXTx) outcomes and to identify potential effects of OCXTx on cardiac physiology. We used the Affymetrix GeneChip Porcine Genomic Array to characterize three types of orthotopic cardiac xenograft outcomes: 1) rejected hearts that underwent delayed xenograft rejection (DXR); 2) survivor hearts in which the xenograft was not rejected and recipient death was due to model complications; and 3) hearts which failed to provide sufficient circulatory support within the first 48 h of transplant, termed "perioperative cardiac xenograft dysfunction" (PCXD). Gene expression in each group was compared to control, not transplanted pig hearts, and changes in gene expression > 3 standard deviations (±3SD) from the control samples were analyzed. A bioinformatics analysis was used to identify enrichments in genes involved in Kyoto Encyclopedia of Genes and Genomes pathways and gene ontogeny molecular functions. Changes in gene expression were confirmed by quantitative RT-PCR. The ±3SD data set contained 260 probes, which minimally exhibited a 3.5-fold change in gene expression compared to control pig hearts. Hierarchical cluster analysis segregated rejected, survivor and PCXD samples, indicating a unique change in gene expression for each group. All transplant outcomes shared a set of 21 probes with similarly altered expression, which were indicative of ongoing myocardial inflammation and injury. Some outcome-specific changes in gene expression were identified. Bioinformatics analysis detected an enrichment of genes involved in protein, carbohydrate and branched amino acid metabolism, extracellular matrix-receptor interactions, focal adhesion, and cell communication. This is the first genome wide assessment of changes in cardiac gene expression after OCXTx. Hierarchical cluster analysis indicates a unique gene profile for each transplant outcome but additional samples will be required to define the unique classifier probe sets. Quantitative RT-PCR confirmed that all transplants exhibited strong evidence of ongoing inflammation and myocardial injury consistent with the effects of cytokines and vascular antibody-mediated inflammation. This was also consistent with bioinformatic analysis suggesting ongoing tissue repair in survivor and PCXD samples. Bioinformatics analysis suggests for the first time that xenotransplantation may affect cardiac metabolism in survivor and rejected samples. This study highlights the potential utility of molecular analysis to monitor xenograft function, to identify new molecular markers and to understand processes, which may contribute to DXR.

Background: NMDA-R-hypofunction (NRH) is considered one of the putative molecular mechanism involved in psychosis. Several studies show that an imbalance of dopamine–glutamate transmission has a key role in psychosis pathophysiology. Preclinical and clinical data indicate that NMDA-Rs antagonists may affect cortical and striatal pathways and animal models of NRH suggest profound changes in synaptic gene expression and in expression of genes involved in neural glucose metabolism. Our aim was to investigate the molecular changes putatively occurring in multiple biological systems in an animal model that has been widely used to resemble psychotic-like behaviors in preclinical studies. Methods: 1) Gene expression of Hk1 (coding for the enzyme catalyzing glycolysis) and GLUT3 (coding for the main membrane transporter involved in glucose intake within neurons) were investigated in an acute paradigm after the administration of Ketamine (12mg/kg and 50mg/kg). 2) Gene expression of D1R-D2R-DAT were investigated in an acute paradigm after the administration of Ketamine (12mg/kg and 50mg/kg) and in a subchronic paradigm after the administration of ketamine (12mg/kg). 3) Gene expression of PSD-genes (Homer 1a, Homer 1b, Arc and PSD-95) and c-fos were investigated in an acute paradigm after the administration of Memantine (5mg/kg), MK-801 (0,8mg/kg), Ketamine (25mg/kg and 50mg/kg). We used male Sprague-Dawley rats and performed In Situ Hybridization Histochemistry in order to analyze gene expression for its quantitative and topographical pattern. Results: Glucose metabolism may be impaired by ketamine, causing an increase in the expression of Hk1 gene, and a decrease in the expression of the GLUT3 as adaptive changes in glucose metabolism; acute ketamine reduces D1R expression while subchronic ketamine increases dopamine D2R and DAT expression as feedback mechanism to avoid hyperdopaminergia; memantine induces different and somewhat opposite molecular changes in PSD gene expression when compared to the fully NMDA-R antagonists ketamine and MK-801 activating, probably, divergent intracellular pathways and so explaining the divergent clinical outcomes of these compounds. Conclusions: The overall conclusion that stems from the different paradigms investigated in this study and based on subanaesthetic ketamine administration model of psychosis in rats is that multiple changes in gene expression occur after NMDA-R-blockade in cortical and subcortical regions and affect the transcription of genes involved in glucose metabolism and dopamine-glutamate interaction.

Because the respiratory chain is the major site of oxidation of the reduced equivalents and of energy production in aerobic cells, its inhibition has severe impact on the cells. Communication pathways from the respiratory chain are required to allow the cell to sense the defect and respond to it. In this work, we studied changes in gene expression induced by the treatment of yeast cells with myxothiazol, an inhibitor of the bc(1) complex, an enzyme of the respiratory chain. The pattern and time-course expression of the genes resemble those of the environmental stress response, a common gene expression program induced by sudden changes in the environment. In addition, the changes were, for most of the genes, mediated through the transcription factors Msn2/4, which play a central role in the cellular response to these stresses. By using a mutant with a myxothiazol-resistant bc(1) complex, we showed that the changes of expression of the majority of the genes was caused by the inhibition of the bc(1) complex but that other stresses might be involved. The expression pattern of CTT1, coding for a cytoplasmic catalase, was further studied. The expression of this gene was largely dependent on Msn2/4 and the inhibition of the cytochrome bc(1). Addition of oxidants of NADH was found to decrease the expression of CTT1 induced by myxothiazol treatment, suggesting that the accumulation of NADH caused by the inhibition of the respiratory chain may be involved in the signaling pathway from the mitochondria to the transcription factor.

The most common cause of chronic heart failure in the US is secondary or primary dilated cardiomyopathy (DCM). The DCM phenotype exhibits changes in the expression of genes that regulate contractile function and pathologic hypertrophy. However, it is unclear if any of these alterations in gene expression are disease producing or modifying. One approach to providing evidence for cause-effect of a disease-influencing gene is to quantitatively compare changes in phenotype to changes in gene expression by employing serial measurements in a longitudinal experimental design. We investigated the quantitative relationships between changes in gene expression and phenotype n 47 patients with idiopathic DCM. In endomyocardial biopsies at baseline and 6 months later, we measured mRNA expression of genes regulating contractile function (beta-adrenergic receptors, sarcoplasmic reticulum Ca(2) + ATPase, and alpha- and beta-myosin heavy chain isoforms) or associated with pathologic hypertrophy (beta-myosin heavy chain and atrial natriuretic peptide), plus beta-adrenergic receptor protein expression. Left ventricular phenotype was assessed by radionuclide ejection fraction. Improvement in DCM phenotype was directly related to a coordinate increase in alpha- and a decrease in beta-myosin heavy chain mRNA expression. In contrast, modification of phenotype was unrelated to changes in the expression of beta(1)- or beta(2)-adrenergic receptor mRNA or protein, or to the mRNA expression of sarcoplasmic reticulum Ca(2) + ATPase and atrial natriuretic peptide. We conclude that in human DCM, phenotypic modification is selectively associated with myosin heavy chain isoform changes. These data support the hypothesis that myosin heavy chain isoform changes contribute to disease progression in human DCM.

Editorial FocusEpigenetic changes in gene expression: focus on "The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction"Barbara T. AlexanderBarbara T. AlexanderPublished Online:01 Feb 2010https://doi.org/10.1152/ajpregu.00760.2009This is the final version - click for previous versionMoreSectionsPDF (180 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations the term epigenetics was first coined in 1942 by Waddington (20) to describe the interaction of genes with their environment during development that gives rise to a phenotype. Today, the term epigenetics is used when describing a phenotype that occurs in a manner outside conventional genetic interactions and refers to stable and heritable alterations in gene expression that do not involve a change in DNA sequence (9). DNA methylation is one type of epigenetic mechanism that serves as a postreplication modification and can occur in response to environmental influences (14). DNA methylation, which involves the modification of cytosines found in the dinucleotide sequence CpG (9), can activate or suppress transcription, is reversible (9), and plays a critical role in normal mammalian cell differentiation and development (14). DNA methylation is also implicated in the pathology of many age-related diseases, such as cancer (6), and, importantly, epigenetic modification of the genome can allow for stable transmission of gene activity to the next generation (9).Developmental origins of health and disease (DOHaD) refers to the process by which the phenotype of a fetus is altered in response to environmental influences (2). The DOHaD hypothesis originated from a geographical correlation of infant mortality and ischemic heart disease (2). Based on this study, Barker (2) proposed that adverse environmental influences during early development permanently alter the body's structure, function, and metabolism in ways that lead to an increased risk for adult cardiovascular and metabolic disease. Numerous epidemiological studies now validate this association, and numerous experimental studies have investigated potential mechanisms involved in the DOHaD (1); however, the exact link between fetal life and programmed adult disease remains unclear. Although the increased risk of adult health and disease observed in a fetus exposed to environmental stresses implicates epigenetic processes as a possible link (Figure 1), few studies have directly tested this hypothesis.Fig. 1.DNA methylation of a gene is a type of epigenetic process that can occur in response to adverse environmental influences. Changes in gene expression associated with an increased risk for adult disease occur in response to adverse environmental influences during critical periods of development. Thus, epigenetic processes may serve as a critical link between insults during fetal life and the increased risk for adult disease.Download figureDownload PowerPointThe rodent model of maternal low protein is well characterized as an experimental model of DOHaD (10). Protein is key for proper fetal growth (3) and a reduction in protein content from a range of 18% to 20% to a range of 9% to 12% in the maternal diet can lead to disproportionate fetal growth, hypertension, cardiovascular disease, and metabolic programming in low-protein offspring (1, 3, 10, 19). In addition, reductions in birth weight (3), cardiovascular dysfunction (19), and programmed alterations in methylation of hepatic gene promoters (4) can extend to the next generation. Thus, the mechanism by which maternal low protein leads to DOHaD may involve epigenetic effects mediated via altered DNA methylation of key genes linked to health and disease.Temporal alterations in lipid metabolism are noted in low-protein offspring; similar hepatic triglyceride and cholesterol content are observed at 1 mo of age (5) but increase in low-protein offspring with age relative to control (5). Hepatic lipid homeostasis is regulated by a number of nuclear receptors including the peroxisome proliferator-activated receptor-α (PPARα) and the liver X-receptor (LXR) (11). PPARα and LXR are activated by free fatty acids and cholesterol metabolites, respectively, and they modulate lipid homeostasis by activating target genes (8) that initiate the synthesis and uptake of cholesterol, fatty acids, and triglycerides (see Refs. 7 or 16 for a complete review). An earlier study by Lillycrop et al. (12) reported that a reduction in methylation of CpG dinucleotides in the PPARα nuclear receptor in 28-day-old offspring of low-protein dams is associated with an increase in expression of PPARα mRNA and its target gene, Acyl-CoA oxidase. Whether hypomethylation of the PPARα gene and increased gene expression persist into adulthood, and whether these changes in gene expression are associated with dysregulation of lipid metabolism are not addressed. However, these findings indicate that epigenetic regulation of the hepatic PPARα gene can occur in response to a fetal insult and suggests a potential link between adverse influences during fetal life and later adult health.Although epigenetic processes, such as changes in gene methylation, are known mediators of transcriptional activation and repression (9), whether the specific hypomethylation pattern of the PPARα gene induced by maternal low protein in offspring can directly influence PPARα gene expression was not determined in the previous study by Lillycrop et al. (12). van Straten et al. (17) utilize the DOHaD model of maternal low protein to demonstrate epigenetic modification of another nuclear receptor critical for lipid homeostasis, the LXR. In response to prenatal exposure to low protein, a specific pattern of hypermethylation of CpG dinucleotides in the fetal liver LXR alpha gene promoter was observed at embryonic day 19.5 (E19.5) in low-protein offspring and importantly, was associated with reduced expression of the fetal hepatic LXR alpha gene (17). In addition, expression of LXR alpha target genes, which contribute to cholesterol elimination, such as the ATP-binding cassette transporters ABCG5 and ABCG8, were also reduced (17). The causal relationship between the specific pattern of CpG hypermethylation of the LXR gene identified in this study and changes in LXR gene expression was directly tested in vitro by use of pharmacological and reporter gene expression assay methodologies (17). Notably, van Straten et al. observed that the specific hypermethylation pattern of the LXR gene induced in response to maternal low protein resulted in a reduction in gene expression in vitro (17). Thus, this study provides further evidence that epigenetic effects may serve as a critical link between the fetal response to a nutritional insult and later adult disease.However, the overall importance of epigenetic modification of a gene and the transmission of changes in gene expression into pathophysiological relevance is still not clear. In the current study by van Straten et al. (17) reduced expression of the fetal hepatic LXR gene and other genes involved in cholesterol excretion was associated with a decrease in fetal hepatic cholesterol content. In adult mice lacking the LXR alpha receptor, hepatic cholesterol is elevated in response to a dietary challenge of 2% cholesterol, suggesting that LXR alpha play a critical role in adult hepatic cholesterol homeostasis (7). Thus, suppression of fetal hepatic LXR alpha gene expression and its target genes was not associated with an increase in fetal hepatic cholesterol content. Cholesterol is critical for many processes during fetal development (15) and the fetus obtains its cholesterol from both endogenous and exogenous sources (21). Expression of rodent fetal hepatic LXR alpha peaks at E18 (15) and previous work by van Straten et al. demonstrate that LXR induced expression of hepatic ABCG5 and ABCG8 is functional in fetal mice (18). However, placental LXR and its target genes may also contribute to cholesterol homeostasis in the fetus (13), and therefore, the importance of programmed changes in the fetal hepatic LXR pathway on fetal lipid homeostasis is not yet clear. Additionally, whether programmed hypermethylation of the LXR alpha gene persists beyond fetal life is reversed, and/or contributes to changes in adult hepatic cholesterol content and later adult disease are important questions that remain to be tested.To conclude, the study by van Straten et al. (17) provides critical evidence that modulation of a gene by an epigenetic process, such as DNA methylation in response to fetal insult can alter gene expression. Whether these specific epigenetic modifications persist long term, contribute to later reprogramming of the LXR gene and its target genes, or contribute to an increased risk for adult disease is not yet known. Moreover, whether passage of an epigenetic modification to the next generation is of pathophysiological significance remains unanswered. Hypomethylation of the hepatic PPARα gene in offspring (F1) of maternal low-protein dams persists into adulthood (12) and is transmitted to the next generation (F2) (4). Yet, hypomethylation of the PPARα gene does not translate into an increase in PPARα gene expression in F2 offspring (4). Clearly, additional studies are required to comprehensively address the importance of transgenerational effects of epigenetic mechanisms in the DOHaD. Investigation of these parameters will be critical in determining the overall importance of epigenetic processes as a potential link between fetal responses to environmental influences, the programming of adult health and disease, and the heritable risk of disease in the next generation.GRANTSB. T. Alexander is supported by National Heart, Lung, and Blood Institute Grants HL-074927 and HL-51971.DISCLOSURESNo conflicts of interest are declared by the author.REFERENCES1. Alexander BT . Fetal programming of hypertension. Am J Physiol Regul Integr Comp Physiol 290: R1–R10, 2006.Link | ISI | Google Scholar2. Barker DJ . The origins of the development origins theory. J Intern Med 261: 412–417, 2007.Crossref | PubMed | ISI | Google Scholar3. Bertram CE , Hanson MA . Animal models and programming of the metabolic syndrome. Br Med Bull 60: 103–121, 2001.Crossref | PubMed | ISI | Google Scholar4. Burdge GC , Slater-Jefferies J , Torrens C , Phillips ES , Hanson MA , Lillycrop KA . Dietary protein restriction of pregnant rats in the F0 generation induces altered methylation of hepatic gene promoters in the adult male offspring in the F1 and F2 generations. Br J Nutr 97: 435–439, 2007.Crossref | PubMed | ISI | Google Scholar5. Erhuma A , Salter AM , Sculley DV , Langtey-Evans SC , Bennett AJ . Prenatal exposure to a low-protein diet programs disordered regulation of lipid metabolism in the aging rat. Am J Physiol Endocrinol Metab 292: E1702–E1714, 2007.Link | ISI | Google Scholar6. Esteller M . Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8: 286–298, 2007.Crossref | PubMed | ISI | Google Scholar7. Gabbi C , Warner M , Gustafsson JA . Liver X receptor B: emerging roles in the physiology and diseases. Mol Endocrinol 23: 129–136, 2009.Crossref | PubMed | Google Scholar8. Hong C , Tontonoz P . Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors. Curr Opin Genet Dev 18: 461–467, 2008.Crossref | PubMed | ISI | Google Scholar9. Jaenisch R , Bird A . Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33, Suppl: 245–254, 2003.Crossref | PubMed | ISI | Google Scholar10. Langley-Evans SC . Fetal programming of cardiovascular function through exposure to maternal undernutrition. Proc Nutr Soc 60: 505–513, 2001.Crossref | PubMed | ISI | Google Scholar11. Li AC , Glass CK . PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. J Lipid Res 45: 2161–2173, 2004.Crossref | PubMed | ISI | Google Scholar12. Lillycrop KA , Phillips ES , Torrens C , Hanson MA , Jackson AA , Burdge GC . Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring. Br J Nutr 100: 278–282, 2008.Crossref | PubMed | ISI | Google Scholar13. Plösch T , van Straten EM , Kuipers F . Cholesterol transport by the placenta: placental liver X receptor activity as a modulator of fetal cholesterol metabolism? Placenta 28: 604–610, 2007.Crossref | PubMed | ISI | Google Scholar14. Reik W , Dean W , Walter J . Epigenetic reprogramming in mammalian development. Science 293: 1089–1093, 2001.Crossref | PubMed | ISI | Google Scholar15. Sakamoto A , Kawasaki T , Kazawa T , Ohashi R , Jiang S , Maejima T , Tanaka T , Iwanari H , Hamakubo T , Sakai J , Kodama T , Naito M . Expression of liver X receptor alpha in rat fetal tissues at different developmental stages. J Histochem Cytochem 55: 641–649, 2007.Crossref | PubMed | ISI | Google Scholar16. Steffensen KR , Gustafsson JA . Putative metabolic effects of the liver X receptor (LXR). Diabetes 53, Suppl 1: S36–S42, 2004.Crossref | PubMed | ISI | Google Scholar17. van Straten EME , Bloks VW , Huijkman NCA , Baller JFW , van Meer H , Lütjohann D , Kuipers F , Plösch T . The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction. Am J Physiol Regul Integr Comp Physiol (11 4, 2009). doi: 10.1152/ajpregu.00413.2009.PubMed | ISI | Google Scholar18. van Straten EM , Huijkman NC , Baller JF , Kuipers F , Plösch T . Pharmacological activation of LXR in utero directly influences ABC transporter expression and function in mice but does not affect adult cholesterol metabolism. Am J Physiol Endocrinol Metab 295: E1341–E1348, 2008.Link | ISI | Google Scholar19. Vehaskari VM , Woods LL . Prenatal programming of hypertension: lessons from experimental models. J Am Soc Nephrol 16: 2545–2556; 2005.Crossref | PubMed | ISI | Google Scholar20. Waddington CH . The epigenotype. Endeavour 1: 18–20, 1942.Google Scholar21. Wollett LA . Fetal lipid metabolism. Front Biosci 6: D536–D545, 2001.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: B. T. Alexander, Dept. of Physiology and Biophysics, Univ. of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216-4505 (e-mail: [email protected]umsmed.edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByDNA methylation as a regulator of intestinal gene expression15 February 2021 | British Journal of Nutrition, Vol. 126, No. 11Perinatal high methyl donor alters gene expression in IGF system in male offspring without altering DNA methylationFuture Science OA, Vol. 3, No. 1Sugared water consumption by adult offspring of mothers fed a protein-restricted diet during pregnancy results in increased offspring adiposity: the second hit effect14 October 2013 | British Journal of Nutrition, Vol. 111, No. 4Regulation of Early Human Growth: Impact on Long-Term Health18 November 2014 | Annals of Nutrition and Metabolism, Vol. 65, No. 2-3 More from this issue > Volume 298Issue 2February 2010Pages R272-R274 Copyright & PermissionsCopyright © 2010 the American Physiological Societyhttps://doi.org/10.1152/ajpregu.00760.2009PubMed19955491History Received 16 November 2009 Accepted 30 November 2009 Published online 1 February 2010 Published in print 1 February 2010 Metrics

BackgroundMounting evidence supports the contribution of neurotrophic herpesvirus family infections to Alzheimer’s Disease (AD) etiology on the molecular, physiologic, and epidemiologic levels. As chronic viral infections have substantial variability in reactivations, and AD pathology is known to begin over a decade prior to symptoms, understanding the longitudinal impact of herpesviruses on AD pathogenesis is a challenging and complex problem.MethodWe developed a mouse model of herpes‐simplex virus type 1 (HSV‐1) infection in C57B6/J mice containing humanized APP and APOE4. Using 10 mice per group (5 male, 5 female), and after initial infection at 2 months of age via corneal scarification with 106 PFU HSV‐1 strain 17, we reactivated the virus with the bromo‐domain compound JQ1 at 4, 6 and 10 months, with 1x, 3x and 6x reactivations respectively. We included both mock transfected and JQ1‐only treated mice as controls.ResultWe found reactivation by JQ1 resulted in increased HSV‐1 detection by qPCR in a progressive manner, emanating outward from the trigeminal ganglion, towards more distal brain regions. One month post reactivation, we harvested multiple brain regions (brainstem, hippocampus, entorhinal cortex, and dural sinus) for RNAseq expression profiling one month after the last reactivation (i.e. latent HSV‐1 infection) to allow for the immune system to clear the active reactivation and observe long‐term changes in gene expression. We found many synaptic genes down regulated in the entorhinal cortex at 10 months, with 6 reactivations, compared to mock infected. We additionally saw decreases in gene expression in lipid metabolism, myelination, and the endolysosomal pathways. In the brain stem, where HSV‐1 viral levels were found at higher levels, gene expression patterns showed increase immune‐cell related activity.ConclusionOur HSV‐1 reactivation mouse model enables characterization of the impacts of HSV‐1 infections on neuronal gene expression. These changes are consistent with observed changes in gene expression in humans, and help contextualize the putative mechanisms by which HSV‐1 contribute to Alzheimer’s disease etiology.

A result of the ongoing opioid epidemic has been a significant rise in the rates of opioid use during pregnancy. This includes use of maintenance medications for opioid use disorder (MOUDs), such as methadone, which are the standard of care for pregnant people with an opioid use disorder (OUD). Although the use of MOUDs leads to better neonatal outcomes in exposed offspring compared to those born from individuals with untreated OUD, the pharmacology of MOUDs is similar to misused opioids. Despite the high prevalence of prenatal exposure to opioids, including MOUDs, our understanding of the long-term consequences of these exposures in offspring is limited. Prenatal drug exposure is known to be a risk factor for future substance use disorder and mood disorders, yet, how prenatal opioid exposure influences ethanol intake in adult offspring and associated affective behaviors has not been examined. Using a rat model of prenatal methadone exposure (PME), which included twice daily methadone injections from gestational day 3-20, this study assessed ethanol intake in adult offspring and how exposure to forced swim stress (FSS) altered ethanol intake, in addition to examination of depressive-like behavior during the FSS. Given the role of the basolateral amygdala (BLA) in emotion and reward processing, we also conducted patch clamp electrophysiology experiments from BLA neurons to investigate changes in synaptic transmission and gene expression of neuromodulatory systems that are known to influence emotion and reward processing. Females with a history of PME consumed less ethanol than control females, with no effects of PME on ethanol intake evident in males. While PME increased immobility during FSS in both males and females, FSS had no effects on ethanol intake. PME increased glutamate transmission and altered dopamine D1, D2, and D3 receptor and mu opioid receptor mRNA in the BLA of females, but not in males. Collectively, this study identified impairments in emotion and reward processing, in addition to alterations in synaptic function and gene expression in the BLA of females with a history of PME, supporting previous findings from our lab demonstrating that female offspring are more sensitive to the long-term effects of PME.

Detecting and treating Alzheimer's disease, before cognitive deficits occur, has become the health challenge of our time. The earliest known event in Alzheimer's disease is rising amyloid-β. Previous studies have suggested that effects on synaptic transmission may precede plaque deposition. Here we report how relative levels of different soluble amyloid-β peptides in hippocampus, preceding plaque deposition, relate to synaptic and genomic changes. Immunoprecipitation-mass spectrometry was used to measure the early rise of different amyloid-β peptides in a mouse model of increasing amyloid-β ('TASTPM', transgenic for familial Alzheimer's disease genes APP/PSEN1). In the third postnatal week, several amyloid-β peptides were above the limit of detection, including amyloid-β40, amyloid-β38 and amyloid-β42 with an intensity ratio of 6:3:2, respectively. By 2 months amyloid-β levels had only increased by 50% and although the ratio of the different peptides remained constant, the first changes in synaptic currents, compared to wild-type mice could be detected with patch-clamp recordings. Between 2 and 4 months old, levels of amyloid-β40 rose by ∼7-fold, but amyloid-β42 rose by 25-fold, increasing the amyloid-β42:amyloid-β40 ratio to 1:1. Only at 4 months did plaque deposition become detectable and only in some mice; however, synaptic changes were evident in all hippocampal fields. These changes included increased glutamate release probability (P < 0.001, n = 7-9; consistent with the proposed physiological effect of amyloid-β) and loss of spontaneous action potential-mediated activity in the cornu ammonis 1 (CA1) and dentate gyrus regions of the hippocampus (P < 0.001, n = 7). Hence synaptic changes occur when the amyloid-β levels and amyloid-β42:amyloid-β40 ratio are still low compared to those necessary for plaque deposition. Genome-wide microarray analysis revealed changes in gene expression at 2-4 months including synaptic genes being strongly affected but often showing significant changes only by 4 months. We thus demonstrate that, in a mouse model of rising amyloid-β, the initial deposition of plaques does not occur until several months after the first amyloid-β becomes detectable but coincides with a rapid acceleration in the rise of amyloid-β levels and the amyloid-β42:amyloid-β40 ratio. Prior to acceleration, however, there is already a pronounced synaptic dysfunction, reflected as changes in synaptic transmission and altered gene expression, indicating that restoring synaptic function early in the disease progression may represent the earliest possible target for intervention in the onset of Alzheimer's disease.

Chapter 9 - Changes in cortical gene expression in major depressive disorders: More evidence implicating inflammatory-related pathways in disease etiology

Loss of NRF2 leads to impaired mitochondrial function, decreased synaptic density and exacerbated age-related cognitive deficits

Memory formation is associated with constant modifications of neuronal networks and synaptic plasticity gene expression in response to different environmental stimuli and experiences. Dysregulation of synaptic plasticity gene expression affects memory during aging and neurodegenerative diseases. Covalent modifications such as methylation on DNA and acetylation on histones regulate the transcription of synaptic plasticity genes. Changes in these epigenetic marks correlated with alteration of synaptic plasticity gene expression and memory formation during aging. These epigenetic modifications, in turn, are regulated by physiology and metabolism. Steroid hormone estrogen and metabolites such as S-adenosyl methionine and acetyl CoA directly impact DNA and histones' methylation and acetylation levels. Thus, the decline of estrogen levels or imbalance of these metabolites affects gene expression and underlying brain functions. In the present review, we discussed the importance of DNA methylation and histone acetylation on chromatin modifications, regulation of synaptic plasticity gene expression and memory consolidation, and modulation of these epigenetic marks by epigenetic modifiers such as phytochemicals and vitamins. Further, understanding the molecular mechanisms that modulate these epigenetic modifications will help develop recovery approaches.