Browsing by Subject "alzheimer's disease"
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Item Epigenetic Regulation of Gene Expression in Alzheimer’s disease(2016-05-01) Shewale, Shantanu J.; John V. Planz; Arthur J. EisenbergAlzheimer’s disease (AD) is the most common form of age-related neurodegenerative dementia, and it is estimated that over 5 million people currently have AD within United States. AD can either be early onset or Late Onset AD (LOAD). Early onset AD has an age of onset below 60 years, and LOAD has an age of onset of above 65 years. Early onset AD accounts for 95% of AD cases, and numerous genetic loci have been linked to LOAD; these loci have small effect sizes, and explain only 50% of AD risk. We hypothesize that epigenetic mechanisms are responsible for a significant portion of this missing heritability. The impact of epigenetic mechanisms on AD risk and progression are relatively unexplored, and should be considered when addressing a portion of the remaining missing heritability. Within this project, post mortem frontal cortex brain tissue from 11 AD patients and 12 age matched controls were used to investigate DNA methylation and differential gene expression in AD. Since post mortem human tissue was used, preliminary analysis showed presence of degraded RNA, most likely due to post mortem intervals. To combat degraded RNA, a novel library preparation process was utilized prior to performing RNA sequencing. DNA methylation was investigated using two methods. For site specific investigation, the Illumina® Infinium HumanMethylation450 BeadChip array was utilized. To investigate differential methylated regions, a Methyl-Binding Protein capture approach was used to precipitate out methylated regions of the genome. This precipitated DNA was then analyzed for methylated regions by using high throughput sequencing. The Differentially Expressed Genes (DEGs) found within our RNA-seq dataset all elucidate the importance of some previously suspected pathways involved in the pathogenesis of AD. Gene Ontology (GO) analysis performed indicate that DEGs implicate numerous genes correlated with neurological disease, and collectively effect regulation of synaptic transmission, cell-cell signaling, neurotransmitter transport, genes involved in the inflammatory response, and Amyloid Precursor Protein (APP) processing. The overlap of 32 DEGs and differentially methylated CpGs was observed. GO analysis demonstrated the same GO terms (synaptic transmission & cell-cell signaling) impacted within both, RNA and DNA datasets. This indicates a link between CpG methylation and differential gene expression.Item INTERACTION OF APOE GENOTYPE, ANTIOXIDANTS AND EXERCISE ON BRAIN FUNCTION.(2014-03) Chaudhari, Kiran; Wong, Jessica M.; Vann, Philip H.; Sumien, NathalieHuge rise in the incidence of azheimer's disease is projected with baby boomers' retiring age. There are very few drugs in market to manage this condition. Doctors and care takers often depend on the lifestyle modification to assist the definitive drug therapy. Most common form of lifestyle modification is exercise and diet rich in antioxidants. Further, APOE4 is a gene that is commonly expressed and a well established genetic risk factor for Alzheimer's development. We identified role of gender and APOE4 in affecting the benefits of lifestyle modification. We used a mouse model that express human APOE4 and develops memory loss at early age. This model is routinely used for alzheimer's disease related experiments. We treated these mice with treadmill based exercise and fed them with diet rich in antioxidants like vitamin C and vitamin E. After treatment these mice were tested for learning and memory abilities using interesting and non stressful techniques that involve swimming, running on rotating rod etc. We found that exercise and antioxidants are more beneficial in combination in only some of the tests. The benefits of the combination of exercise and antioxidants depends on sex, APOE genotype and age of the mouse. Purpose (a): The ε4 allele of apolipoprotein E (ApoE) has been associated with increased risk for the development of late-onset Alzheimer’s disease (AD). To prevent or reduce the appearance of brain dysfunction, a healthy lifestyle, such as exercising and eating antioxidants, is often recommended. Physical activity has been shown to have an allele-specific beneficial effect on cognition in humans and rodents. Antioxidant therapy is often suggested to improve brain function, as increased oxidative stress has been correlated with brain dysfunction, especially in ε4 carriers. Health conscious individuals are likely to combine exercise with antioxidant intake to increase protection; however recent studies have indicated a potential negative interaction of these two factors. In some cases, antioxidant intake abolished the beneficial effects of exercise. Our study aimed at determining the nature of the interaction between exercise and antioxidants on functional outcomes in a model of increased AD risk. Methods (b): Male and female mice (12month), expressing the human ApoE3 or E4, were placed under one of the treatment: Sedentary/control diet (SedCon), Sedentary /antioxidant-rich diet (Vitamins E-195mg/kg body weight/day and C-287mg/kg body weight/day; SedEC), Exercise/control diet (ExCon), Exercise/ antioxidant-rich diet (ExEC), for 8 weeks prior to behavioral testing including coordinated running (rotorod), spatial learning and memory (Morris water maze) and discriminated avoidance (T-maze). Results (c): Overall, ApoE3 mice performed better than ApoE4 mice on the rotorod test and ExEC treatment improved the performance of the male ApoE3 only. The ExEC treatment improved spatial learning in both male and female ApoE4 mice, whereas ExCon improved performance only in the ApoE4 females. Maximum spatial learning was improved with ExEC in males regardless of genotype but only in the ApoE3 females. In the discriminated avoidance task, initial learning was improved with ExCon treatment in ApoE3 mice regardless of gender. Cognitive flexibility was improved by ExEC treatment in ApoE3 male and female and in ApoE4 females but not in male ApoE4. Conclusions (d): These results indicate that genotype and sex are critical determinants in the functional outcomes of the treatment regimens.Item Mechanisms by which 17β-Estradiol (E2) suppress neuronal cox-2 expression(2015-12-01) Stacey, Winfred; Rosalie M. Uht; Rebecca L. Cunningham; Eric B. GonzalesData from animal models indicate that 17β-estradiol (E2) deprivation increases susceptibility to neurodegenerative diseases. E2 attenuates inflammatory response by suppressing expression of pro-inflammatory genes; however, the mechanisms by which E2 suppress neuronal pro-inflammatory genes are not well established. Histological analyses of postmortem human brains suggest that neuronal cyclooxygenase-2 (COX-2) is upregulated in early stages of Alzheimer’s disease (AD) and in Parkinson’s disease (PD). Given that COX-2 is selectively expressed in a subset of neurons in the hippocampus, cerebral cortex, and amygdala, we investigated mechanisms by which E2 could down-regulate cox-2 expression in a neuronal system. To characterize the effect of E2 on cox 2 in a neuronal system, we used the AR-5 and N27 rat neuronal cell line models. Our data indicate that E2 and ERβ agonist diarylpropionitrile (DPN) suppress COX-2 pre-mRNA and mRNA levels to the same extent in AR-5 but not in N27. Furthermore, PHTPP, a selective ERβ antagonist, reversed the effect of both E2 and DPN in AR-5. Because the cox-2 promoter lacks palindromic estrogen response elements (EREs), we targeted a proximal promoter region with a nuclear factor- ĸB (NF-ĸB) response element implicated in cox-2 regulation. E2 and DPN failed to increase ERβ occupancy at the cox-2 promoter. Rather, DPN decreased promoter occupancy of p65 NF-κB subunit and acetylation of histone 4 (Ac-H4). Treatment with the non-specific HDAC inhibitor Trichostatin A (TSA) counteracted DPN’s repressive effects on cox-2 expression. In keeping with the effect of TSA, E2 and DPN increase HDAC1 promoter occupancy; however recruitment of HDAC3 was unchanged. HDAC1 is known to form a complex with Swi-independent A (Sin3A); E2 and DPN increased Sin3A occupancy. The recruitment of HDAC1 seems to correlate with decreased acetylation of histone 4 (H4) and not histone 3 (H3). Furthermore E2 alone increased methylation status in the cox-2 proximal promoter. Taken together, these data suggest that E2 suppresses neuronal cox-2 expression through ERβ-mediated recruitment of HDAC1, Sin3A and a concomitant reduction of p65 and H4 levels. Here we conclude that E2 suppresses neuronal cox-2 expression through a mechanism that involves a combination of decreasing activator and increasing repressor recruitment to the cox-2 promoter.