Functional characterization of three single‐nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA–protein interactions

Variations in levels of apolipoprotein E (ApoE) have been tied to the risk and progression of Alzheimer's disease (AD). Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene (APOE) 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 (A/T), −427 (T/C), and at −219 (G/T) upstream from the +1 transcription start site. The −219 and −491 polymorphic variations have significant association with instance of AD, and −491AA has significant risk even when stratified for the APOEε4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The −491 and −219 polymorphisms may have an interactive effect in addition to any independent activity. DNA–protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the −491 and −219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA–protein interactions in cell culture‐based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEε4 allele status. © 2009 Wiley‐Liss, Inc.

[1]  N. Zawia,et al.  Lifespan profiles of Alzheimer's disease-associated genes and products in monkeys and mice. , 2009, Journal of Alzheimer's disease : JAD.

[2]  G. J. Harry,et al.  Lifespan profiles of Alzheimer ' s disease – associated genes and their products in monkeys and mice , 2016 .

[3]  Demao Chen,et al.  Alzheimer's Disease (AD)-Like Pathology in Aged Monkeys after Infantile Exposure to Environmental Metal Lead (Pb): Evidence for a Developmental Origin and Environmental Link for AD , 2008, The Journal of Neuroscience.

[4]  G. J. Harry,et al.  Co-localization and distribution of cerebral APP and SP1 and its relationship to amyloidogenesis. , 2008, Journal of Alzheimer's disease : JAD.

[5]  Bryan Maloney,et al.  Important differences between human and mouse APOE gene promoters: limitation of mouse APOE model in studying Alzheimer’s disease , 2007, Journal of neurochemistry.

[6]  K. Morgan,et al.  Regulatory region single nucleotide polymorphisms of the apolipoprotein E gene and the rate of cognitive decline in Alzheimer's disease. , 2007, Human molecular genetics.

[7]  W. Walker,et al.  SP1 transcription factors in male germ cell development and differentiation , 2007, Molecular and Cellular Endocrinology.

[8]  N. Zawia,et al.  How and when environmental agents and dietary factors affect the course of Alzheimer's disease: the "LEARn" model (latent early-life associated regulation) may explain the triggering of AD. , 2007, Current Alzheimer research.

[9]  D. Blacker,et al.  Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database , 2007, Nature Genetics.

[10]  D. Lahiri.  Apolipoprotein E as a target for developing new therapeutics for Alzheimer’s disease based on studies from protein, RNA, and regulatory region of the gene , 2007, Journal of Molecular Neuroscience.

[11]  Bryan Maloney,et al.  Genes are not our destiny: the somatic epitype bridges between the genotype and the phenotype , 2006, Nature Reviews Neuroscience.

[12]  O. Gureje,et al.  Cholesterol, APOE genotype, and Alzheimer disease , 2006, Neurology.

[13]  J. Hardy,et al.  Characterization of two APP gene promoter polymorphisms that appear to influence risk of late-onset Alzheimer's disease , 2005, Neurobiology of Aging.

[14]  M. Bullido,et al.  Neuronal specific regulatory elements in apolipoprotein E gene proximal promoter , 2005, Neuroreport.

[15]  D. Mann,et al.  Is there a relation between APOE expression and brain amyloid load in Alzheimer’s disease? , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[16]  Miki Ohira,et al.  LMO3 interacts with neuronal transcription factor, HEN2, and acts as an oncogene in neuroblastoma. , 2005, Cancer research.

[17]  S. Paul,et al.  NF-κB mediates amyloid β peptide-stimulated activity of the human apolipoprotein E gene promoter in human astroglial cells , 2005 .

[18]  Sun Young Lee,et al.  Decrease in NF-κB, AP-1 and SP-1 activities in neuronal cells expressing presenilin 2 , 2005, Neuroreport.

[19]  R. Basha,et al.  The Fetal Basis of Amyloidogenesis: Exposure to Lead and Latent Overexpression of Amyloid Precursor Protein and β-Amyloid in the Aging Brain , 2005, Journal of Neuroscience.

[20]  S. Paul,et al.  NF-(kappa)B mediates amyloid beta peptide-stimulated activity of the human apolipoprotein E gene promoter in human astroglial cells. , 2005, Brain research. Molecular brain research.

[21]  D. Lahiri.  Functional Characterization of Amyloid β Precursor Protein Regulatory Elements: Rationale for the Identification of Genetic Polymorphism , 2004, Annals of the New York Academy of Sciences.

[22]  Bryan Maloney,et al.  Mechanism of promoter activity of the β‐amyloid precursor protein gene in different cell lines: identification of a specific 30 bp fragment in the proximal promoter region , 2004, Journal of neurochemistry.

[23]  Lin Feng,et al.  APOE and APOC1 promoter polymorphisms and the risk of Alzheimer disease in African American and Caribbean Hispanic individuals. , 2004, Archives of neurology.

[24]  N. Greig,et al.  Cholesterol and Alzheimer's disease: clinical and experimental models suggest interactions of different genetic, dietary and environmental risk factors. , 2004, Current drug targets.

[25]  J. Lambert,et al.  APOE promoter polymorphisms and dementia in the elderly , 2004, Neuroscience Letters.

[26]  W. Miller,et al.  GATA-4 and GATA-6 modulate tissue-specific transcription of the human gene for P450c17 by direct interaction with Sp1. , 2004, Molecular endocrinology.

[27]  D. Lahiri,et al.  Efficient DNA transfection in neuronal and astrocytic cell lines , 2000, Molecular Biology Reports.

[28]  K. Takimoto,et al.  GATA and FOG2 transcription factors differentially regulate the promoter for Kv4.2 K(+) channel gene in cardiac myocytes and PC12 cells. , 2003, Cardiovascular research.

[29]  J. Yunis,et al.  Haplogroup analysis of the risk associated with APOE promoter polymorphisms (−219T/G, −491A/T and −427T/C) in Colombian Alzheimer's disease patients , 2003, Neuroscience Letters.

[30]  N. Zawia,et al.  Intracellular signaling pathways involved in mediating the effects of lead on the transcription factor Sp1 , 2003, International Journal of Developmental Neuroscience.

[31]  D. Bennett,et al.  Alzheimer disease in the US population: prevalence estimates using the 2000 census. , 2003, Archives of neurology.

[32]  L. Thal,et al.  Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology , 2003, Neurology.

[33]  F. Gaunitz,et al.  Cloning and expression of the rat BACE1 promoter , 2003, Journal of neuroscience research.

[34]  Y. Ge,et al.  Functional Characterization of the 5′‐Regulatory Region of the Murine Apolipoprotein Gene , 2002, Annals of the New York Academy of Sciences.

[35]  D. Hernandez,et al.  Contribution of APOE promoter polymorphisms to Alzheimer’s disease risk , 2002, Neurology.

[36]  A Hofman,et al.  Effect of the APOE-491A/T promoter polymorphism on apolipoprotein E levels and risk of Alzheimer disease: The Rotterdam Study. , 2002, American journal of medical genetics.

[37]  J. Mate,et al.  The Th1/E47cs-G apolipoprotein E (APOE) promoter allele is a risk factor for Alzheimer disease of very later onset , 2002, Neuroscience Letters.

[38]  David Simon,et al.  ApoE genotype, past adult lead exposure, and neurobehavioral function. , 2002, Environmental health perspectives.

[39]  D. Sparks,et al.  Water quality has a pronounced effect on cholesterol-induced accumulation of Alzheimer amyloid beta (Abeta) in rabbit brain. , 2002, Journal of Alzheimer's disease : JAD.

[40]  R. Martins,et al.  APOE-epsilon4 and APOE -491A polymorphisms in individuals with subjective memory loss. , 2002, Molecular psychiatry.

[41]  R. Martins,et al.  APOE-ε4 and APOE −491A polymorphisms in individuals with subjective memory loss , 2002, Molecular Psychiatry.

[42]  D. Campion,et al.  APOE promoter polymorphisms do not confer independent risk for Alzheimer's disease in a French population , 2000, European Journal of Human Genetics.

[43]  B. Cisneros,et al.  Sp1 and AP2 transcription factors are required for the human fragile mental retardation promoter activity in SK-N-SH neuronal cells , 1999, Neuroscience Letters.

[44]  M. Franceschi,et al.  APOE −491 promoter polymorphism is a risk factor for late-onset Alzheimer’s disease , 1999, Neurology.

[45]  J. Gewirtz,et al.  Polymorphisms of the human apolipoprotein E promoter and bleomycin hydrolase gene: risk factors for Alzheimer's dementia? , 1999, Neuroscience Letters.

[46]  H. Kawakami,et al.  Apolipoprotein E promoter polymorphism and sporadic Alzheimer's disease in a Japanese population , 1999, Neuroscience Letters.

[47]  A. Hofman,et al.  The −491 A/T polymorphism in the regulatory region of the Apolipoprotein E gene and early-onset Alzheimer's disease , 1998, Neuroscience Letters.

[48]  M. Emmerling,et al.  Elevated low-density lipoprotein in Alzheimer's disease correlates with brain abeta 1-42 levels. , 1998, Biochemical and biophysical research communications.

[49]  A. Goate,et al.  Risk for Alzheimer's disease correlates with transcriptional activity of the APOE gene. , 1998, Human molecular genetics.

[50]  J. Hardy,et al.  Pronounced impact of Th1/E47cs mutation compared with -491 AT mutation on neural APOE gene expression and risk of developing Alzheimer's disease. , 1998, Human molecular genetics.

[51]  D. Lahiri.  An region upstream of the gene promoter for the beta-amyloid precursor protein interacts with proteins from nuclear extracts of the human brain and PC12 cells. , 1998, Brain research. Molecular brain research.

[52]  M. Bullido,et al.  Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene , 1998, FEBS letters.

[53]  J. Morris,et al.  A polymorphism in the regulatory region of APOE associated with risk for Alzheimer's dementia , 1998, Nature Genetics.

[54]  D. Seshasayee,et al.  Functional interaction of GATA1 with erythroid Krüppel-like factor and Sp1 at defined erythroid promoters. , 1996, Blood.

[55]  H. Brewer,et al.  Amyloid-associated proteins α1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer β-protein into filaments , 1994, Nature.

[56]  John Hardy,et al.  Single-day apolipoprotein E genotyping , 1994, Journal of Neuroscience Methods.

[57]  D. Lahiri,et al.  Tacrine alters the secretion of the beta‐amyloid precursor protein in cell lines , 1994, Journal of neuroscience research.

[58]  Stephen W. Scheff,et al.  Induction of Alzheimer-like β-Amyloid Immunoreactivity in the Brains of Rabbits with Dietary Cholesterol , 1994, Experimental Neurology.

[59]  J. Ma,et al.  Amyloid-associated proteins alpha 1-antichymotrypsin and apolipoprotein E promote assembly of Alzheimer beta-protein into filaments. , 1994, Nature.

[60]  J. Haines,et al.  Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. , 1993, Science.

[61]  A. D. Roses,et al.  Association of apolipoprotein E allele €4 with late-onset familial and sporadic Alzheimer’s disease , 2006 .

[62]  M A Pericak-Vance,et al.  Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. , 1993, Neurology.

[63]  J. Nurnberger,et al.  A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. , 1991, Nucleic acids research.