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  • Original Research Article
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Regulatory region variability in the human presenilin-2 (PSEN2) gene: potential contribution to the gene activity and risk for AD

Molecular Psychiatry volume 7, pages 891–898 (2002)Cite this article

Abstract

We have analyzed the 5′-upstream promoter region of the presenilin 2 gene (PSEN2) for regulatory elements and examined Alzheimer disease (AD) patients and non-demented individuals for polymorphisms in the 5′ upstream promoter region of the PSEN2 gene. Direct sequencing analysis detected a common single adenine (A) nucleotide deletion polymorphism in the upstream promoter region of the PSEN2 gene. Examination of cohorts of AD patients and age-matched control individuals revealed no statistically significant differences in the frequency of this polymorphism when compared with the total sample of AD patients and control individuals. However, subgroup and regression analysis suggested that the relatively rare −A/−A genotype increases risk of AD among subjects lacking apolipoprotein E (APOE) ε4 and among persons ages 65 years and younger. DNA sequence and DNA-protein binding analysis demonstrated that this mutation negates binding with putative repressor transcription factor (TF), interferon regulatory factor 2 (IRF2), in nuclear extracts prepared from the aged human brain neocortex. However this mutation creates a potential regulatory element, C/EBPbeta, that is responsive to pro-inflammatory (PI) induction. The expression activity assay with luciferase reporter gene into normal human neural progenitor cells in primary culture shows that the mutant PSEN2 regulatory region exhibits a 1.8-fold higher level of basal expression and is sensitive to IL−1β and Aβ42, but that it is synergistically induced 3.2-fold over the wild-type PSEN2 by [IL−1β+Aβ42]. These results suggest that under Pl and oxygen stress conditions relatively minor variations in PSEN2 promoter DNA sequence structure can enhance PSEN2 gene expression and that consequently these may play a role in the induction and/or proliferation of a Pl response in AD brain.

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Acknowledgements

This work was supported by grants from the Howard Hughes Medical Institute, INTAS, European Commission Inco-Copernicus, Russian Fund for Basic Research, Russian Home Genome Program, NIH FIRCA, NIH AG18031, NIH AG09029, NIH AG95004, NIH NS23002, the Fogarty Center at NIH, and the EENT Foundation of Louisiana. Authors would like to thank to SI Gavrilova, N Selezneva, V Golimbet, A Lujnikova for assistance in collection of specimens of AD patients and elderly control subjects and I Chumakov for assistance in screening for 5′-regions of presenilins.

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Author notes

  1. N Riazanskaia and W J Lukiw: N Riazanskaia and W Lukiw contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Molecular Brain Genetics, Research Center of Mental Health, Russian Academy of Medical Sciences of Russia, Moscow, 113152, Russia

    N Riazanskaia, A Grigorenko, G Korovaitseva, G Dvoryanchikov, Y Moliaka & El Rogaev

  2. Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, 70112–2272, Louisiana, USA

    W J Lukiw & N G Bazan

  3. Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, 70112–2272, Louisiana, USA

    W J Lukiw & N G Bazan

  4. Institute of Molecular Genetics, Russian Academy of Sciences, Moscow

    A Grigorenko

  5. Department of Medicine (Genetics Program) and Dept of Neurology, Boston University School of Medicine, Boston, MA, USA

    M Nicolaou & L Farrer

  6. Department of Epidemiology and Biostatistics, Boston University School of Public Health, Boston, MA, USA

    L Farrer

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  1. N Riazanskaia
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Correspondence to El Rogaev.

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Riazanskaia, N., Lukiw, W., Grigorenko, A. et al. Regulatory region variability in the human presenilin-2 (PSEN2) gene: potential contribution to the gene activity and risk for AD. Mol Psychiatry 7, 891–898 (2002). https://doi.org/10.1038/sj.mp.4001101

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