Bryan Maloney Indiana University Purdue University, Indianapolis
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  1. C. A. Erickson, B. Ray, B. Maloney, L. K. Wink, K. Bowers, T. L. Schaefer, C. J. McDougle, D. K. Sokol & D. K. Lahiri (2014). Impact of Acamprosate on Plasma Amyloid-Beta Precursor Protein in Youth: A Pilot Analysis in Fragile X Syndrome-Associated and Idiopathic Autism Spectrum Disorder Suggests a Pharmacodynamic Protein Marker. J Psychiatr Res 59:220-8.
    BACKGROUND: Understanding of the pathophysiology of autism spectrum disorder remains limited. Brain overgrowth has been hypothesized to be associated with the development of ASD. A derivative of amyloid-beta precursor protein , secreted APPalpha , has neuroproliferative effects and has been shown to be elevated in the plasma of persons with ASD compared to control subjects. Reduction in sAPPalpha holds promise as a novel molecular target of treatment in ASD. Research into the neurochemistry of ASD has repeatedly implicated excessive glutamatergic and (...)
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  2. D. K. Lahiri, B. Maloney, J. M. Long & N. H. Greig (2014). Lessons From a BACE1 Inhibitor Trial: Off-Site but Not Off Base. Alzheimers Dement 10:S411-9.
    Alzheimer's disease is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-beta peptide . The rate-limiting step in the production of Abeta is the processing of Abeta precursor protein by beta-site APP-cleaving enzyme . Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Abeta within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was (...)
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  3. F. P. Perez, D. Bose, B. Maloney, K. Nho, K. Shah & D. K. Lahiri (2014). Late-Onset Alzheimer's Disease, Heating Up and Foxed by Several Proteins: Pathomolecular Effects of the Aging Process. J Alzheimers Dis 40:1-17.
    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 (...)
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  4. D. K. Lahiri, B. Maloney, J. T. Rogers & Y. W. Ge (2013). PuF, an Antimetastatic and Developmental Signaling Protein, Interacts with the Alzheimer's Amyloid-Beta Precursor Protein Via a Tissue-Specific Proximal Regulatory Element. Bmc Genomics 14:68.
    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 (...)
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  5. D. K. Lahiri, D. K. Sokol, C. Erickson, B. Ray, C. Y. Ho & B. Maloney (2013). Autism as Early Neurodevelopmental Disorder: Evidence for an sAPPalpha-Mediated Anabolic Pathway. Front Cell Neurosci 7:94.
    Autism is a neurodevelopmental disorder marked by social skills and communication deficits and interfering repetitive behavior. Intellectual disability often accompanies autism. In addition to behavioral deficits, autism is characterized by neuropathology and brain overgrowth. Increased intracranial volume often accompanies this brain growth. We have found that the Alzheimer's disease associated amyloid-beta precursor protein , especially its neuroprotective processing product, secreted APP alpha, is elevated in persons with autism. This has led to the "anabolic hypothesis" of autism etiology, in which neuronal (...)
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  6. S. W. Bihaqi, A. Schumacher, B. Maloney, D. K. Lahiri & N. H. Zawia (2012). Do Epigenetic Pathways Initiate Late Onset Alzheimer Disease : Towards a New Paradigm. Curr Alzheimer Res 9:574-88.
    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 (...)
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  7. D. K. Lahiri & B. Maloney (2012). Gene X Environment Interaction by a Longitudinal Epigenome-Wide Association Study Overcomes Limitations of Genome-Wide Association Study. Epigenomics 4:685-99.
    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 (...)
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  8. D. K. Lahiri & B. Maloney (2012). The "LEARn" Model: An Epigenetic Pathway Linking Metabolic and Cognitive Disorders. J Alzheimers Dis 30:S15-30.
    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 (...)
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  9. B. Maloney & D. K. Lahiri (2012). Structural and Functional Characterization of H2 Haplotype MAPT Promoter: Unique Neurospecific Domains and a Hypoxia-Inducible Element Would Enhance Rationally Targeted Tauopathy Research for Alzheimer's Disease. Gene 501:63-78.
    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 (...)
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  10. B. Maloney, K. Sambamurti, N. Zawia & D. K. Lahiri (2012). Applying Epigenetics to Alzheimer's Disease Via the Latent Early-Life Associated Regulation Model. Curr Alzheimer Res 9:589-99.
    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, (...)
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  11. J. A. Bailey, B. Maloney, Y. W. Ge & D. K. Lahiri (2011). Functional Activity of the Novel Alzheimer's Amyloid Beta-Peptide Interacting Domain in the APP and BACE1 Promoter Sequences and Implications in Activating Apoptotic Genes and in Amyloidogenesis. Gene 488:13-22.
    Amyloid-beta peptide plaque in the brain is the primary diagnostic criterion of Alzheimer's disease . The physiological role of Abeta are poorly understood. We have previously determined an Abeta interacting domain in the promoters of AD-associated genes . This AbetaID interacts in a DNA sequence-specific manner with Abeta. We now demonstrate novel Abeta activity as a possible transcription factor. Herein, we detected Abeta-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma cells treated with FITC conjugated Abeta1-40 (...)
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  12. B. Maloney & D. K. Lahiri (2011). The Alzheimer's Amyloid Beta-Peptide Binds a Specific DNA Abeta-Interacting Domain in the APP, BACE1, and APOE Promoters in a Sequence-Specific Manner: Characterizing a New Regulatory Motif. Gene 488:1-12.
    Deposition of extracellular plaques, primarily consisting of amyloid beta peptide , in the brain is the confirmatory diagnostic of Alzheimer's disease ; however, the physiological and pathological role of Abeta is not fully understood. Herein, we demonstrate novel Abeta activity as a putative transcription factor upon AD-associated genes. We used oligomers from 5'-flanking regions of the apolipoprotein E , Abeta-precursor protein and beta-amyloid site cleaving enzyme-1 genes for electrophoretic mobility shift assay with different fragments of the Abeta peptide. Our results (...)
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  13. D. K. Sokol, B. Maloney, J. M. Long, B. Ray & D. K. Lahiri (2011). Autism, Alzheimer Disease, and Fragile X: APP, FMRP, and mGluR5 Are Molecular Links. Neurology 76:1344-52.
    The present review highlights an association between autism, Alzheimer disease , and fragile X syndrome . We propose a conceptual framework involving the amyloid-beta peptide , Abeta precursor protein , and fragile X mental retardation protein based on experimental evidence. The anabolic effect of the secreted alpha form of the amyloid-beta precursor protein may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPalpha levels associate with more severe symptoms of (...)
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  14. D. K. Lahiri & B. Maloney (2010). Beyond the Signaling Effect Role of Amyloid-Ss42 on the Processing of APP, and its Clinical Implications. Exp Neurol 225:51-4.
    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 (...)
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  15. D. K. Lahiri & B. Maloney (2010). The "LEARn" Model Integrates Environmental Risk Factors and the Developmental Basis of Alzheimer's Disease, and Proposes Remedial Steps. Exp Gerontol 45:291-6.
    The neurodegenerative disorder Alzheimer's disease is the 6th leading cause of death in the USA. In addition to neurological and psychiatric symptoms, AD is characterized by deficiencies in S-adenylmethionine , vitamin B12, and folate. Deficiency in these nutrients has been shown to result in gene promoter methylation with upregulation of AD-associated genes. While some cases of AD are due to specific mutations in genes such as presenilin 1 and the amyloid-beta peptide precursor protein , these familial AD cases account for (...)
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  16. B. Maloney, Y. W. Ge, R. C. Petersen, J. Hardy, J. T. Rogers, J. Perez-Tur & D. K. Lahiri (2010). Functional Characterization of Three Single-Nucleotide Polymorphisms Present in the Human APOE Promoter Sequence: Differential Effects in Neuronal Cells and on DNA-Protein Interactions. Am J Med Genet B Neuropsychiatr Genet 153:185-201.
    Variations in levels of apolipoprotein E have been tied to the risk and progression of Alzheimer's disease . Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 , -427 , and at -219 upstream from the (...)
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  17. R. Dosunmu, J. Wu, L. Adwan, B. Maloney, M. R. Basha, C. A. McPherson, G. J. Harry, D. C. Rice, N. H. Zawia & D. K. Lahiri (2009). Lifespan Profiles of Alzheimer's Disease-Associated Genes and Products in Monkeys and Mice. J Alzheimers Dis 18:211-30.
    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 (...)
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  18. Debomoy K. Lahiri, Bryan Maloney & Nasser H. Zawia (2009). The LEARn Model: An Epigenetic Explanation for Idiopathic Neurobiological Diseases. Molecular Psychiatry 14 (11):992-1003.
    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 (...)
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  19. B. Maloney, B. Ray, E. P. Hayden, J. I. Nurnberger Jr & D. K. Lahiri (2009). Development and Validation of the High-Quality 'Rapid Method for Swab' to Genotype the HTTLPR Serotonin Transporter Promoter Polymorphism. Psychiatr Genet 19:72-82.
    BACKGROUND: The importance of genetic variation to the etiology of neuropsychiatric disorders is well established and is currently being examined for diagnosis and treatment. The most popular method of obtaining material for genotype analysis, high-yielding DNA extraction from blood, has several limitations, including invasiveness, need for skilled individuals to collect material, and requirement for cold storage. Saliva sampling is noninvasive and trained personnel are less necessary, but it still requires a relatively high level of subject compliance. Buccal mucosa cells sampling (...)
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  20. B. Brock, R. Basha, K. DiPalma, A. Anderson, G. J. Harry, D. C. Rice, B. Maloney, D. K. Lahiri & N. H. Zawia (2008). Co-Localization and Distribution of Cerebral APP and SP1 and its Relationship to Amyloidogenesis. J Alzheimers Dis 13:71-80.
    Alzheimer's disease is characterized by amyloid-beta peptide -loaded plaques in the brain. Abeta is a cleavage fragment of amyloid-beta protein precursor and over production of APP may lead to amyloidogenesis. The regulatory region of the APP gene contains consensus sites recognized by the transcription factor, specificity protein 1 , which has been shown to be required for the regulation of APP and Abeta. To understand the role of SP1 in APP biogenesis, herein we have characterized the relative distribution and localization (...)
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  21. E. P. Hayden, L. R. Dougherty, B. Maloney, T. M. Olino, H. Sheikh, C. E. Durbin, J. I. Nurnberger Jr, D. K. Lahiri & D. N. Klein (2008). Early-Emerging Cognitive Vulnerability to Depression and the Serotonin Transporter Promoter Region Polymorphism. J Affect Disord 107:227-30.
    BACKGROUND: Serotonin transporter promoter genotype appears to increase risk for depression in the context of stressful life events. However, the effects of this genotype on measures of stress sensitivity are poorly understood. Therefore, this study examined whether 5-HTTLPR genotype was associated with negative information processing biases in early childhood. METHOD: Thirty-nine unselected seven-year-old children completed a negative mood induction procedure and a Self-Referent Encoding Task designed to measure positive and negative schematic processing. Children were also genotyped for the 5-HTTLPR gene. (...)
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  22. D. K. Lahiri, N. H. Zawia, N. H. Greig, K. Sambamurti & B. Maloney (2008). Early-Life Events May Trigger Biochemical Pathways for Alzheimer's Disease: The "LEARn" Model. Biogerontology 9:375-9.
    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. (...)
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  23. Y. Wen, W. H. Yu, B. Maloney, J. Bailey, J. Ma, I. Marie, T. Maurin, L. Wang, H. Figueroa, M. Herman, P. Krishnamurthy, L. Liu, E. Planel, L. F. Lau, D. K. Lahiri & K. Duff (2008). Transcriptional Regulation of Beta-Secretase by P25/Cdk5 Leads to Enhanced Amyloidogenic Processing. Neuron 57:680-90.
    Cyclin-dependent kinase 5 has been implicated in Alzheimer's disease pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a (...)
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  24. J. Wu, M. R. Basha, B. Brock, D. P. Cox, F. Cardozo-Pelaez, C. A. McPherson, J. Harry, D. C. Rice, B. Maloney, D. Chen, D. K. Lahiri & N. H. Zawia (2008). Alzheimer's Disease -Like Pathology in Aged Monkeys After Infantile Exposure to Environmental Metal Lead : Evidence for a Developmental Origin and Environmental Link for AD. J Neurosci 28:3-9.
    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 (...)
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  25. E. P. Hayden, L. R. Dougherty, B. Maloney, C. Emily Durbin, T. M. Olino, J. I. Nurnberger Jr, D. K. Lahiri & D. N. Klein (2007). Temperamental Fearfulness in Childhood and the Serotonin Transporter Promoter Region Polymorphism: A Multimethod Association Study. Psychiatr Genet 17:135-42.
    OBJECTIVES: Early-emerging, temperamental differences in fear-related traits may be a heritable vulnerability factor for anxiety disorders. Previous research indicates that the serotonin transporter promoter region polymorphism is a candidate gene for such traits. METHODS: Associations between 5-HTTLPR genotype and indices of fearful child temperament, derived from maternal report and standardized laboratory observations, were examined in a community sample of 95 preschool-aged children. RESULTS: Children with one or more long alleles of the 5-HTTLPR gene were rated as significantly more nervous during (...)
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  26. D. K. Lahiri, D. Chen, B. Maloney, H. W. Holloway, Q. S. Yu, T. Utsuki, T. Giordano, K. Sambamurti & N. H. Greig (2007). The Experimental Alzheimer's Disease Drug Posiphen [-Phenserine] Lowers Amyloid-Beta Peptide Levels in Cell Culture and Mice. J Pharmacol Exp Ther 320:386-96.
    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, (...)
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  27. D. K. Lahiri, B. Maloney, M. R. Basha, Y. W. Ge & N. H. Zawia (2007). How and When Environmental Agents and Dietary Factors Affect the Course of Alzheimer's Disease: The "LEARn" Model May Explain the Triggering of AD. Curr Alzheimer Res 4:219-28.
    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 (...)
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  28. B. Maloney, Y. W. Ge, G. M. Alley & D. K. Lahiri (2007). Important Differences Between Human and Mouse APOE Gene Promoters: Limitation of Mouse APOE Model in Studying Alzheimer's Disease. J Neurochem 103:1237-57.
    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 (...)
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  29. C. M. Bolin, R. Basha, D. Cox, N. H. Zawia, B. Maloney, D. K. Lahiri & F. Cardozo-Pelaez (2006). Exposure to Lead and the Developmental Origin of Oxidative DNA Damage in the Aging Brain. Faseb J 20:788-90.
    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 (...)
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  30. D. K. Lahiri, Y. W. Ge, J. T. Rogers, K. Sambamurti, N. H. Greig & B. Maloney (2006). Taking Down the Unindicted Co-Conspirators of Amyloid Beta-Peptide-Mediated Neuronal Death: Shared Gene Regulation of BACE1 and APP Genes Interacting with CREB, Fe65 and YY1 Transcription Factors. [REVIEW] Curr Alzheimer Res 3:475-83.
    Major hallmarks of Alzheimer's disease include brain deposition of the amyloid-beta peptide , which is proteolytically cleaved from a large Abeta precursor protein by beta and gamma- secretases. A transmembrane aspartyl protease, beta-APP cleaving enzyme , has been recognized as the beta-secretase. We review the structure and function of the BACE1 protein, and of 4129 bp of the 5'-flanking region sequence of the BACE1 gene and its interaction with various transcription factors involved in cell signaling. The promoter region and 5'-untranslated (...)
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  31. D. K. Lahiri, B. Maloney & Y. W. Ge (2006). BACE1 Gene Promoter is Differentially Regulated: Detection of a Novel Promoter Region for its Cell Type-Specific Regulation. J Mol Neurosci 28:193-210.
    The amyloid-beta peptide, the proteolytic fragment of Abeta precursor protein , aggregates and forms neuritic plaques, a major hallmark of Alzheimer's disease . The limiting step in generating the Abeta peptide from APP is cleavage by the beta-secretase enzyme, BACE1. Regulation of the BACE1 gene is likely to play an important role in AD etiology and treatment. We therefore studied the activity of a 4.1-kb 5'-flanking region of the BACE1 gene, both in 5'- and 3'-deletion series and through Northern blotting. (...)
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  32. D. K. Lahiri, B. Maloney & Y. W. Ge (2006). Functional Domains of the BACE1 and BACE2 Promoters and Mechanisms of Transcriptional Suppression of the BACE2 Promoter in Normal Neuronal Cells. [REVIEW] J Mol Neurosci 29:65-80.
    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 (...)
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  33. B. Maloney, Y. W. Ge, N. H. Greig & D. K. Lahiri (2006). Characterization of the Human Beta-Secretase 2 5'-Flanking Region: Identification of a 268-Bp Region as the Basal BACE2 Promoter. [REVIEW] J Mol Neurosci 29:81-99.
    The main characteristic of Alzheimer's disease is brain deposition of the beta-amyloid peptide, generated endoproteolytically from Abeta precursor protein by beta- and gamma-secretases. A transmembrane aspartyl protease, beta-APP-cleaving enzyme , was identified as beta-secretase. Although BACE1 cleaves APP at the beta-secretase site, the role of its homolog, beta-secretase 2 is poorly understood. We report the mRNA expression profile, DNA sequence, and molecular characterization of the BACE2 gene, located on chromosome 21q22.3. The BACE2 gene expresses more strongly in peripheral tissues, although (...)
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  34. D. K. Sokol, D. Chen, M. R. Farlow, D. W. Dunn, B. Maloney, J. A. Zimmer & D. K. Lahiri (2006). High Levels of Alzheimer Beta-Amyloid Precursor Protein in Children with Severely Autistic Behavior and Aggression. J Child Neurol 21:444-9.
    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 (...)
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  35. Y. Du, X. Chen, X. Wei, K. R. Bales, D. T. Berg, S. M. Paul, M. R. Farlow, B. Maloney, Y. W. Ge & D. K. Lahiri (2005). NF-B Mediates Amyloid Beta Peptide-Stimulated Activity of the Human Apolipoprotein E Gene Promoter in Human Astroglial Cells. Brain Res Mol Brain Res 136:177-88.
    The apolipoprotein E gene plays an important role in the pathogenesis of Alzheimer's disease , and amyloid plaque comprised mostly of the amyloid-beta peptide ) is one of the major hallmarks of AD. However, the relationship between these two important molecules is poorly understood. We examined how A treatment affects APOE expression in cultured cells and tested the role of the transcription factor NF-B in APOE gene regulation. To delineate NF-B's role, we have characterized a 1098 nucleotide segment containing the (...)
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  36. D. K. Lahiri, Y. W. Ge & B. Maloney (2005). Characterization of the APP Proximal Promoter and 5'-Untranslated Regions: Identification of Cell Type-Specific Domains and Implications in APP Gene Expression and Alzheimer's Disease. Faseb J 19:653-5.
    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 (...)
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  37. D. K. Lahiri, Y. W. Ge, B. Maloney, F. Wavrant-De Vrieze & J. Hardy (2005). Characterization of Two APP Gene Promoter Polymorphisms That Appear to Influence Risk of Late-Onset Alzheimer's Disease. Neurobiol Aging 26:1329-41.
    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 (...)
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  38. S. A. Bellingham, D. K. Lahiri, B. Maloney, S. La Fontaine, G. Multhaup & J. Camakaris (2004). Copper Depletion Down-Regulates Expression of the Alzheimer's Disease Amyloid-Beta Precursor Protein Gene. J Biol Chem 279:20378-86.
    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 (...)
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  39. Y. W. Ge, C. Ghosh, W. Song, B. Maloney & D. K. Lahiri (2004). Mechanism of Promoter Activity of the Beta-Amyloid Precursor Protein Gene in Different Cell Lines: Identification of a Specific 30 Bp Fragment in the Proximal Promoter Region. J Neurochem 90:1432-44.
    The amyloid beta-protein deposited in brains of Alzheimer's disease patients is proteolytically derived from a large Abeta precursor protein . APP gene expression patterns in the AD brain region indicate that abnormalities of gene regulation may be important in AD pathology. To understand the contribution of different cell types to APP gene expression, we studied it at four levels: promoter activity , DNA-nuclear protein interaction , RNA message and protein . APP mRNA and protein expression levels were greater in neuroblastoma (...)
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  40. Y. W. Ge, B. Maloney, K. Sambamurti & D. K. Lahiri (2004). Functional Characterization of the 5' Flanking Region of the BACE Gene: Identification of a 91 Bp Fragment Involved in Basal Level of BACE Promoter Expression. [REVIEW] Faseb J 18:1037-9.
    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 (...)
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  41. B. Maloney, Y. W. Ge, N. Greig & D. K. Lahiri (2004). Presence of a "CAGA Box" in the APP Gene Unique to Amyloid Plaque-Forming Species and Absent in All APLP-1/2 Genes: Implications in Alzheimer's Disease. [REVIEW] Faseb J 18:1288-90.
    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 (...)
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  42. K. Sambamurti, R. Kinsey, B. Maloney, Y. W. Ge & D. K. Lahiri (2004). Gene Structure and Organization of the Human Beta-Secretase Promoter. Faseb J 18:1034-6.
    The first step in the generation of the amyloid-beta peptide deposited in the brains of patients with Alzheimer's disease is the processing of the larger Abeta precursor protein by an integral membrane aspartyl protease named the beta-site APP-cleaving enzyme . We present the genomic organization of the BACE gene. BACE mRNAs are synthesized as nine exons and eight introns from a 30.6 kb region of chromosome 11q23.2-11q23.3. Regulation of BACE may play an important role in regulating the levels of Abeta (...)
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