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Human Molecular Genetics, 2003, Vol. 12, No. 8 869-877
DOI: 10.1093/hmg/ddg098
© 2003 Oxford University Press

Alzheimer-associated C allele of the promoter polymorphism -22C>T causes a critical neuron-specific decrease of presenilin 1 expression

Jessie Theuns1, Jacques Remacle2, Richard Killick3, Ellen Corsmit1, Krist'l Vennekens1, Danny Huylebroeck2, Marc Cruts1 and Christine Van Broeckhoven1,*

1Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp (UIA), Antwerpen, Belgium, 2Department of Developmental Biology, Flanders Interuniversity Institute for Biotechnology (VIB) and Laboratory of Molecular Biology (CELGEN), University of Leuven (KUL), Leuven, Belgium and 3The Institute of Psychiatry, Department of Neuroscience, London, UK

Received December 19, 2002; Accepted February 10, 2003

We, amongst others, have shown that CC homozygosity at the -22C>T promoter polymorphism in presenilin 1 (PSEN1) is associated with increased risk for Alzheimer's disease (AD). Also, studies in AD brains suggested that CC homozygosity increased the risk for AD by increasing the Aß load. We characterized the PSEN1 promoter by deletion mapping, and analysed the effect of the -22C and -22T alleles on the transcriptional activity of PSEN1 in a transient transfection system. We showed a neuron-specific 2-fold decrease in promoter activity for the -22C risk allele, which in homozygous individuals would lead to a critical decrease in PSEN1 expression. The deletion mapping suggested that the 13 bp region (-33/-20) spanning the -22C>T polymorphism harbours a binding site for a negative regulatory factor. This factor has a higher affinity for the -22C risk allele and is strongly dependent on downstream sequences for cell-type-specific expression differences. Together, these studies provide evidence that the increased risk for AD associated with PSEN1 may result from genetic variations in the regulatory region, leading to altered expression levels of PSEN1 in neurons.

* To whom correspondence should be addressed at: Department of Molecular Genetics (VIB8), University of Antwerp (UIA), Universiteitsplein 1, B-2610 Antwerpen, Belgium. Tel: +32 38202601; Fax: +32 38202541; Email: christine.vanbroeckhoven{at}ua.ac.be


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