Bryan Maloney

Oxidative damage to DNA has been associated with neurodegenerative diseases. Developmental exposure to lead has been shown to elevate the Alzheimer's disease related beta-amyloid peptide , which is known to generate reactive oxygen species in the aging brain. This study measures the lifetime cerebral 8-hydroxy-2'-deoxyguanosine levels and the activity of the DNA repair enzyme 8-oxoguanine DNA glycosylase in rats developmentally exposed to Pb. Oxo8dG was transiently modulated early in life , but was later elevated 20 months after exposure to Pb had ceased, while Ogg1 activity was not altered. Furthermore, an age-dependent loss in the inverse correlation between Ogg1 activity and oxo8dG accumulation was observed. The effect of Pb on oxo8dG levels did not occur if animals were exposed to Pb in old age. These increases in DNA damage occurred in the absence of any Pb-induced changes in copper/zinc-superoxide dismutase , manganese-SOD , and reduced-form glutathion . These data suggest that oxidative damage and neurodegeneration in the aging brain could be impacted by the developmental disturbances

Alzheimer's disease is characterized by formation of plaques of amyloid beta peptide . Autosomally-inherited or "familial" AD had been demonstrated only in connection with coding sequence mutations. We characterized DNA-protein interaction and expression influence of two polymorphisms that occur in the promoter of the Abeta precursor protein gene. We report distinct functional differences in reporter expression and in DNA-protein interaction for variant sequences in both -3829 and -1023 polymorphic regions. The -3829T variant has reduced DNA-protein interaction and reporter expression compared to -3829C, while -1023C has greater DNA-protein interaction and reporter expression than -1023T. Our predictions for likely transcription factors for loss of function are ADR1, MIG1, and PuF, and for gain of function are E12/E47, ITF-2, and RFX2. Characterization of the activity of a regulatory polymorphism of the APP gene points towards understanding mechanisms that likely underlie the majority of AD cases and may contribute to promoter-based drug design

The sporadic nature of Alzheimer's disease argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead during brain development predetermined the expression and regulation of the amyloid precursor protein and its amyloidogenic beta-amyloid product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 ] as well as their transcriptional regulator were elevated in aged monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD

Alzheimer's disease is characterized by plaques of amyloid-beta peptide, cleaved from amyloid-beta protein precursor . Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 , and the beta amyloid precursor cleaving enzyme . In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases

Late-onset Alzheimer's disease is the most common neurodegenerative disorder in older adults, affecting over 50% of those over age 85. Aging is the most important risk factor for the development of LOAD. Aging is associated with the decrease in the ability of cells to cope with cellular stress, especially protein aggregation. Here we describe how the process of aging affects pathways that control the processing and degradation of abnormal proteins including amyloid-beta . Genetic association studies in LOAD have successfully identified a large number of genetic variants involved in the development of the disease. However, there is a gap in understanding the interconnections between these pathomolecular events that prevent us from discovering therapeutic targets. We propose novel, pertinent links to elucidate how the biology of aging affects the sequence of events in the development of LOAD. Furthermore we analyze and synthesize the molecular-pathologic-clinical correlations of the aging process, involving the HSF1 and FOXO family pathways, Abeta metabolic pathway, and the different clinical stages of LOAD. Our new model postulates that the aging process would precede Abeta accumulation, and attenuation of HSF1 is an "upstream" event in the cascade that results in excess Abeta and synaptic dysfunction, which may lead to cognitive impairment and/or trigger "downstream" neurodegeneration and synaptic loss. Specific host factors, such as the activity of FOXO family pathways, would mediate the response to Abeta toxicity and the pace of progression toward the clinical manifestations of AD

Autism is characterized by restricted, repetitive behaviors and impairment in socialization and communication. Although no neuropathologic substrate underlying autism has been found, the findings of brain overgrowth via neuroimaging studies and increased levels of brain-derived neurotrophic factor in neuropathologic and blood studies favor an anabolic state. We examined acetylcholinesterase, plasma neuronal proteins, secreted beta-amyloid precursor protein , and amyloid-beta 40 and amyloid-beta 42 peptides in children with and without autism. Children with severe autism and aggression expressed secreted beta-amyloid precursor protein at two or more times the levels of children without autism and up to four times more than children with mild autism. There was a trend for children with autism to show higher levels of secreted beta-amyloid precursor protein and nonamyloidogenic secreted beta-amyloid precursor protein and lower levels of amyloid-beta 40 compared with controls. This favors an increased alpha-secretase pathway in autism , opposite to what is seen in Alzheimer disease. Additionally, a complex relationship between age, acetylcholinesterase, and plasma neuronal markers was found

Potentially toxic amyloid beta-peptide in Alzheimer's disease is generated from a family of Abeta-containing precursor proteins , which is regulated via the 5'-untranslated region of its mRNA. We analyzed 5'-UTRs of the APP superfamily, including amyloid plaque-forming and non-amyloid plaque-forming species, and of prions . A "CAGA" sequence proximal to the "ATG" start codon was present in a location unique to APP genes of amyloid plaque-forming species and absent in all other genes surveyed. This CAGA box is immediately upstream of an interleukin-1-responsive element . In addition, the proximal CAGA box is predicted to appear on a stem-loop structure in both human and guinea pig APP mRNA. This stem-loop is part of a predicted bulge-loop that encompasses a known iron regulatory element . Electrophoretic mobility shift with segments of the APP 5'-UTR showed that a region with the proximal CAGA sequence binds nuclear proteins, and this UTR fragment is active in a reporter gene functional assay. Thus, the 5'-UTR in the human APP but not those of APP-like proteins contains a specific region that may participate in APP regulation and may determine a more general model for amyloid generation as seen in AD. The 5'-UTR of human APP contains several interesting control elements, such as an acute box element, a CAGA box, an IRE, and a transforming growth factor-beta-responsive element, that could control APP expression and provide suitable and specific drug targets for AD

Alzheimer's disease is the leading cause of dementia in the elderly. Extraneuronal plaque comprising mostly the amyloid beta peptide and intraneuronal tangles of hyperphosphorylated microtubule-associated tau protein are typical of AD. Misfolded tau is also implicated in Parkinson's disease and frontotemporal dementia. We aim to understand the regulation of the human MAPT promoter by mapping its functional domains. We subcloned a 4868 base pair fragment from human BAC RPCI-11 100C5. Sequence analysis revealed an H2 haplotype MAPT promoter, 5'-UTR, and intronal fragment. Database analysis of the fragment showed 50%-75% homology with mouse and >90% with rhesus monkey. Comparison with human H1 sequences revealed differences that crossed predicted transcription factor sites. DNA-protein interaction studies by electrophoretic mobility shift assay suggested hypoxia response and an active specificity protein 1 site in the 5'-untranslated region. Transfection of a series of MAPT promoter deletions revealed unique functional domains. The distal-most had different activities in neuronal vs. non-neuronal cells. We have cloned, sequenced, and functionally characterized a 4868bp fragment of the human MAPT 5'-flanking region, including the core promoter region , neurospecific domains , and a hypoxia-inducible element . Our work extended functional analysis of the MAPT sequence further upstream, and explores cell-type specificity of MAPT promoter activity. Finally, we provided direct comparison of likely transcription factor binding sites, which are useful to understand differences between H1/H2 pathogenic associations

Major characteristics of Alzheimer's disease are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid beta-peptide , a proteolytic fragment of amyloid beta precursor protein , aggregates to form neuritic plaques and has a causative role in AD. A present focus of AD research is to develop safe Abeta-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and Abeta. Phenserine is dose-limited in animals by its cholinergic actions; its cholinergically inactive enantiomer, posiphen -[phenserine], was assessed. In cultured human neuroblastoma cells, posiphen, like phenserine, dose- and time-dependently lowered APP and Abeta levels by reducing the APP synthesis rate. This action translated to an in vivo system. Posiphen administration to mice significantly decreased levels of total APP in a dose-dependent manner. Abeta40 and Abeta42 levels were significantly lowered by posiphen compared with controls. The activities of alpha-, beta-, and gamma-secretases were assessed in the same brain samples, and beta-secretase activity was significantly reduced. Posiphen, like phenserine, can lower Abeta via multiple mechanisms and represents an interesting drug candidate for AD treatment

Diabetes, cardiovascular disease, hypertension, and other disorders have been unified within the metabolic syndrome. Recently, it has been proposed that Alzheimer's disease and other degenerative, age-related neurological disorders may also be etiologically linked to the metabolic syndrome in a metabolic-cognitive syndrome. We review current evidence in the field for this unification. In addition, we describe how the latent early-life associated regulation model provides specific mechanisms to predict genetic targets for both metabolic disorders, e.g., diabetes, and neurodegenerative disorders, e.g., AD. The LEARn model is based on environmental induction of latent epigenetic misregulation, which develops into disease upon suffering additional environmental insults. We review structural differences between gene sequences that are and are not susceptible to LEARn misregulation. In addition to suggesting research targets such as the IDE and SORCS1 genes, which are implicated in both AD and diabetes, LEARn suggests specific mechanisms for pre-disease remediation, based on nutritional adjustment of aberrant DNA methylation and oxidation. The possibility of a single metabolic-cognitive disorder opens up the possibility of unified preventative treatments that reduce monetary and social costs of disease. LEARn suggests specific, testable pathways within the large theory

Alzheimer's disease is currently the most prominent form of dementia among the elderly. Although AD manifests in late adult life, it is not clear when the disease actually starts and how long the neuropathological processes take to develop AD. The major unresolved question is the timing and the nature of triggering leading to AD. Is it an early or developmental and/or late phenomenon and what are the factors that trigger the cascade of pathobiochemical processes? To explain the etiology of AD one should consider the neuropathological features, such as neuronal cell death, tau tangles, and amyloid plaque, and environmental factors associated with AD, such as diet, toxicological exposure, and hormonal factors. Current dominant theories of AD etiology are "protein-only", they attribute the cause of the disease directly to the activities of associated proteins once they have been produced; the major limitation is that protein aggregations occur "late in the game". Development and progression of AD has not been explained by protein-only models. In view of this limitation, we propose a "Latent Early-Life Associated Regulation" model, which postulates a latent expression of specific genes triggered at the developmental stage. According to this model, environmental agents , intrinsic factors , and dietary factors perturb gene regulation in a long-term fashion, beginning at early developmental stages; however, these perturbations do not have pathological results until significantly later in life. For example, such actions would perturb APP gene regulation at very early stage via its transcriptional machinery, leading to delayed overexpression of APP and subsequently of Abeta deposition. This model operates on the regulatory region of the gene and by the effect of methylation at certain sites within the promoter of specific genes. Promoters tend to have both positive and negative regulatory elements, and promoter activity can be altered by changes in the primary DNA sequence and by epigenetic changes through mechanisms such as DNA methylation at CpG dinucleotides or oxidation of guanosine residues. The basis of the LEARn model is that environmental factors, including metals and dietary factors, operate by interfering the interaction of methylated CpG clusters with binding proteins, such as MeCP2 and SP1. The LEARn model may explain the etiology of AD and other neuropsychiatric and developmental disorders

Alzheimer's disease is a leading cause of aging related dementia and has been extensively studied by several groups around the world. A general consensus, based on neuropathology, genetics and cellular and animal models, is that the 4 kDa amyloid beta protein triggers a toxic cascade that induces microtubule-associated protein tau hyperphosphorylation and deposition. Together, these lesions lead to neuronal dysfunction and neurodegeneration, modeled in animals, that ultimately causes dementia. Genetic studies show that a simple duplication of the Abeta precursor gene, as occurs in Down syndrome , with a 1.5-fold increase in expression, can cause dementia with the complete AD associated neuropathology. The most fully characterized form of AD is early onset familial AD . Unfortunately, by far the most common form of AD is late onset AD . FAD has well-identified autosomally dominant genetic causes, absent in LOAD. It is reasonable to hypothesize that environmental influences play a much stronger role in etiology of LOAD than of FAD. Since AD pathology in LOAD closely resembles FAD with accumulation of both Abeta and MAPT, it is likely that the environmental factors foster accumulation of these proteins in a manner similar to FAD mutations. Therefore, it is important to identify environmentally driven changes that "phenocopy" FAD in order to find ways to prevent LOAD. Epigenetic changes in expression are complex but stable determinants of many complex traits. Some aspects are regulated by prenatal and early post-natal development, others punctuate specific periods of maturation, and still others occur throughout life, mediating predictable changes that take place during various developmental stages. Environmental agents such as mercury, lead, and pesticides can disrupt the natural epigenetic program and lead to developmental deficits, mental retardation, feminization, and other complex syndromes. In this review we discuss latent early- life associated regulation , where apparently temporary changes, induced by environmental agents, become latent and present themselves again at maturity or senescence to increase production of Abeta that may cause AD. The model provides us with a novel direction for identifying potentially harmful agents that may induce neurodegeneration and dementia later in life and provides hope that we may be able to prevent age-related neurodegenerative disease by "detoxifying" our environment

BACKGROUND: Alzheimer's disease is intimately tied to amyloid-beta peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein account for a small proportion of AD cases, suggesting that regulation of the associated gene may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" , at -76/-47, from the +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 , nm23 nucleoside diphosphate kinase/metastatic inhibitory protein , and specificity protein 1 . These sites crossed a known single nucleotide polymorphism . EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging

Alzheimer's disease currently has over 6 million victims in the USA, alone. The recently FDA approved drugs for AD only provide mild, transient relief for symptoms without addressing underlying mechanisms to a significant extent. Basic understanding of the activities of the amyloid beta peptide and associated proteins such as beta-site APP-cleaving enzyme 1 is necessary to develop effective medical responses to AD. Recently , Tabaton et al. have presented a model of both non-pathological and pathological Abeta activities and suggest potential therapeutic pathways based on their proposed framework of Abeta acting as the signal that induces a kinase cascade, ultimately stimulating transcription factors that upregulate genes such as BACE1. We respond by presenting evidence of Abeta's other activities, including protection against metal-induced reactive oxidizing species , modification of cholesterol transport, and potential activity as a transcription factor in its own right. We touch upon clinical implications of each of these functions and highlight the currently unexplored implications of our suggested novel function of Abeta as a transcription factor. Abeta appears to be a highly multi-functional peptide, and any or all of the pathways it engages in is a likely candidate for antiAD drug development

Alzheimer's disease is characterized by brain deposition of toxic amyloid beta-peptide , generated from the Abeta precursor protein . APP gene expression is regulated via the proximal promoter region and the 5'-untranslated region . We have recently identified a unique CAGA sequence, "amyloid" present only in the APP gene from amyloid plaque-forming species, absent in all APP-like-proteins' genes. To assay functional activity of PPR + UTR and 5'-UTR regions that either contain or lack the "amyloid" box, we tested nine constructs in transient transfection studies. We observed significantly high reporter gene activity with -46/144, -46/100, -46/54, and 54/144 constructs. The 54/100 fragment, which contains a transforming growth factor-beta/ "amyloid"/interleukin-1 acute box cassette, showed different activity depending on cell type. Electrophoretic mobility shift assay showed distinct DNA-nuclear protein interaction in all fragments, differing among both cell types and specific fragment. Reporter gene expression corroborates with the DNA-protein binding pattern. To directly examine the "amyloid" box, we generated oligomers for CAGA mutants or mutated adjacent nucleotides. EMSA results showed that altering "amyloid" or adjacent sequence alters specific DNA-nuclear protein interaction in both mutation- and cell-type-specific manners. Reporter gene assay reveals mutant-specific expression effects. Therefore, the -46/54 region appears to be essential for basal expression of the APP gene, the 54/100 and 100/144 regions may have tissue-specific activity, and the "amyloid" CAGA box plays a role in APP gene regulation

Pathological characteristics of Alzheimer's disease include amyloid-beta plaques. Abeta is derived from the Abeta peptide precursor protein by gamma- and beta-secretases, the latter known as beta-site APP-cleaving enzyme 1 . We have also described potentially important regions in the promoter of BACE, which may regulate its activity . Herein, we have functionally dissected the regulatory regions within the BACE promoter into areas containing positive and negative regulatory elements. The 4.1 kb promoter region includes positive regulatory element in the -2975 to -2062 region flanked on either side by negative regulatory elements at -3764/-2975 and -2062/-1056. This is separated from the minimal promoter and 5' UTR by a neutral region of roughly 700 base pairs . A 91 bp fragment is the shortest region with a significant reporter gene activity and constitutes the minimal promoter element for BACE. Neuronal preference of the promoter was apparent in the 141 bp fragment that contained the 91 bp fragment. Gel shift results also suggest the strongest signal of DNA-protein interaction with the 91 bp fragment in neuronal nuclear extracts. This interaction was strongly blocked by an activator protein 2 binding oligomer. Super gel shift assays suggest that both the AP2-binding oligomer and the 91 bp fragment interfered with each other's binding capacity. An AP2 sequence is predicted to occur within the 91 bp fragment. We also found stimulating protein 1-binding sites in this region of the promoter. Thus, functional and gel shift analysis indicate that the 91 bp fragment containing the AP2 and SP1 binding sites constitutes the core promoter region of BACE. Changes in the activity of this region could play an important role in regulating BACE activity in neurons

Alzheimer's disease is characterized by the accumulation of amyloid-beta peptide, which is cleaved from the amyloid-beta precursor protein . Reduction in levels of the potentially toxic amyloid-beta has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the regulation of the APP gene. Recent in vivo and in vitro studies have illustrated the importance of copper in Alzheimer's disease neuropathogenesis and suggested a role for APP and amyloid-beta in copper homeostasis. We hypothesized that metals and in particular copper might alter APP gene expression. To test the hypothesis, we utilized human fibroblasts overexpressing the Menkes protein , a major mammalian copper efflux protein. MNK deletion fibroblasts have high intracellular copper, whereas MNK overexpressing fibroblasts have severely depleted intracellular copper. We demonstrate that copper depletion significantly reduced APP protein levels and down-regulated APP gene expression. Furthermore, APP promoter deletion constructs identified the copper-regulatory region between -490 and +104 of the APP gene promoter in both basal MNK overexpressing cells and in copper-chelated MNK deletion cells. Overall these data support the hypothesis that copper can regulate APP expression and further support a role for APP to function in copper homeostasis. Copper-regulated APP expression may also provide a potential therapeutic target in Alzheimer's disease

Late onset Alzheimer's disease is a non-familial, progressive neurodegenerative disease and the most prominent form of dementia in the elderly. Accumulating evidence suggests that LOAD not only results from the combined effects of variation in a number of genes and environmental factors, but also from epigenetic abnormalities such as histone modifications or DNA methylation. In comparison to monogenic diseases, LOAD exhibits numerous anomalies that suggest an epigenetic component in disease etiology. Evidence against a monogenic course and for an epigenetic component include: 1) the dominance of sporadic cases over familial ones and the low estimated concordance rates for monozygotic twins; 2) gender specific susceptibility and course of disease; 3) parent-of-origin effects, and late age of onset; 4) brain chromatin abnormalities, non-Mendelian inheritance patterns, and atypical levels of folate and homocysteine; and 5) monoallelic expression patterns of susceptibility genes [1]. The epigenome is particularly susceptible to deregulation during early embryonic and neonatal periods and thus disturbances during these periods can have latent lasting effects. The Latent Early-life Associated Regulation model attempts to explain these consequences from a brain specific point of view. In the present review we present the evidence that support the role of epigenetics in the development of AD and explore the potential pathways and mechanisms that may be involved

Alzheimer's disease , the most common form of dementia among the elderly, manifests mostly late in adult life. However, it is presently unclear when the disease process starts and how long the pathobiochemical processes take to develop. Our goal is to address the timing and nature of triggers that lead to AD. To explain the etiology of AD, we have recently proposed a "Latent Early-life Associated Regulation" model, which postulates a latent expression of specific genes triggered at the developmental stage. This model integrates both the neuropathological features and environmental factors associated with the disease. Environmental agents perturb gene regulation in a long-term fashion, beginning at early developmental stages, but these perturbations do not have pathological results until significantly later in life. The LEARn model operates through the regulatory region of the gene and by affecting the methylation status within the promoter of specific genes

The beta-amyloid protein present in the neuritic plaques of Alzheimer's disease is cleaved from Abeta precursor protein by beta- and gamma-secretases. Following identification of beta-APP cleaving enzyme as the beta-secretase, a homologous beta-secretase 2 was described. Our goal is to characterize the regulatory region of the BACE genes. We compare functional domains within the BACE1 and BACE2 regulatory regions. Both BACE genes lack canonical TATAand CAAT boxes, but they contain distinguishing transcription start sites and transcription factor-binding sites. The BACE1 sequence contains more repetitive elements than does BACE2 . Regulatory domains do not overlap strongly between the two promoter regions. The BACE1upstream sequence contains both negative and positive domains, separated from the transcription seat by a long neutral domain. The corresponding BACE2sequence consists of a weakly positive domain directly upstream of a strongly positive domain, near a functionally active domain. DNA-protein interaction was corroborated by functional data. In primary rat cortical cultures, BACE1-driven reporter protein's expression was twice that of BACE2- driven reporter. The BACE2 gene promoter relatively reduced function in neuronal cells compared with BACE1. The BACE1 gene might operate through a single transcriptional control site. BACE2 operates through dual transcriptional control sites. Two regulatory pathways might control transcription in BACE2. Thus, BACE2 is partially suppressed in normal neuronal cells and likely to be a highly regulated gene expressed in a particularly tissue-specific fashion

The goal of genome-wide association studies is to identify SNPs unique to disease. It usually involves a single sampling from subjects' lifetimes. While primary DNA sequence variation influences gene-expression levels, expression is also influenced by epigenetics, including the 'somatic epitype' ), an epigenotype acquired postnatally. While genes are inherited, and novel polymorphisms do not routinely appear, G is fluid. Furthermore, G could respond to environmental factors and to differences in exercise, maternal care and dietary supplements - all of which postnatally modify oxidation or methylation of DNA, leading to altered gene expression. Change in epigenetic status may be critical for the development of many diseases. We propose a 'longitudinal epigenome-wide association study', wherein G are measured at multiple time points along with subjects' histories. This Longitudinal epigenome-wide association study, based on the 'dynamic' somatic epitype over the 'static' genotype, merits further investigation

Neurobiological disorders have diverse manifestations and symptomology. Neurodegenerative disorders, such as Alzheimer's disease, manifest late in life and are characterized by, among other symptoms, progressive loss of synaptic markers. Developmental disorders, such as autism spectrum, appear in childhood. Neuropsychiatric and affective disorders, such as schizophrenia and major depressive disorder, respectively, have broad ranges of age of onset and symptoms. However, all share uncertain etiologies, with opaque relationships between genes and environment. We propose a 'Latent Early-life Associated Regulation' (LEARn) model, positing latent changes in expression of specific genes initially primed at the developmental stage of life. In this model, environmental agents epigenetically disturb gene regulation in a long-term manner, beginning at early developmental stages, but these perturbations might not have pathological results until significantly later in life. The LEARn model operates through the regulatory region (promoter) of the gene, specifically through changes in methylation and oxidation status within the promoter of specific genes. The LEARn model combines genetic and environmental risk factors in an epigenetic pathway to explain the etiology of the most common, that is, sporadic, forms of neurobiological disorders.

Apolipoprotein E , encoded by the apolipoprotein E gene , plays an important role in the pathogenesis of Alzheimer's disease . The APOE epsilon4 variant is strongly associated with AD. APOE promoter polymorphisms have also been reported to associate with higher AD risk. Mouse models of APOE expression have long been used to study the pathogenesis of AD. Elucidating the role of the APOE gene in AD requires understanding of how its regulation differs between mouse and human APOE genes, and how the differences influence AD risk. We compared the structure and function of both the human APOE gene promoter and mouse APOE gene promoter regions. Homology is less than 40% at 180 bp or more upstream of the two species' transcription start site . Functional analysis revealed both similarities and important differences between the two sequences, significantly affected by human versus rodent cell line origin. We likewise probed nuclear extracts from several cell lines of different origins and mouse brain with specific hAPOEP and mAPOEP fragments. Each fragment shared DNA-protein interactions with the other but, notably, also bound distinct factors, demonstrated by gel shift and southwestern analyses. We determined possible identities for these distinct factors. These results suggest that regulation of mouse and human APOE genes may be sufficiently unique to justify the use of both the human APOE promoter sequence in transgenic rodent models and non-rodent AD models for studying factors involved in AD pathogenesis