Abstract:
: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 Abeta 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.
journal_name
Hum Mol Genetjournal_title
Human molecular geneticsauthors
Theuns J,Remacle J,Killick R,Corsmit E,Vennekens K,Huylebroeck D,Cruts M,Van Broeckhoven Cdoi
10.1093/hmg/ddg098subject
Has Abstractpub_date
2003-04-15 00:00:00pages
869-77issue
8eissn
0964-6906issn
1460-2083journal_volume
12pub_type
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