• Schacherl, J.
• Unger, T.
• Grittner, U.
• Schmerbach, K.
• Walden, P.
• Volkmer, R.
• Goldin-Lang, P.
• Kölsch, H.
• Kintscher, U.
• Kornhuber, J.
• Funke-Kaiser, H.
• Klare, S.
• Reinemund, J.
• Li, Y.
• Hope, A.
• Marschall, P.
• Menk, Mario
• Klein, M.
• Schmitz, J.
• Kirsch, S.
• Hugel, R.
• Scheele, S.
• Schlosser, A.
• Zollmann, F.
• Seidel, K.
• Maier, W.
• Schimkus, J.
• Peters, O.
• Frölich, L.
• Jh, Schefe

Abstract

Genetic factors strongly contribute to the pathogenesis of sporadic Alzheimer's disease (AD). Nevertheless, genome-wide association studies only yielded single nucleotide polymorphism loci of moderate importance. In contrast, microsatellite repeats are functionally less characterized structures within our genomes. Previous work has shown that endothelin-converting enzyme-1 (ECE-1) is able to reduce amyloid β content. Here we demonstrate that a CpG-CA repeat within the human ECE-1c promoter is highly polymorphic, harbors transcriptional start sites, is able to recruit the transcription factors poly(ADP-ribose) polymerase-1 and splicing factor proline and glutamine-rich, and is functional regarding haplotype-specific promoter activity. Furthermore, genotyping of 403 AD patients and 444 controls for CpG-CA repeat length indicated shifted allelic frequency distributions. Sequencing of 245 haplotype clones demonstrated that the overall CpG-CA repeat composition of AD patients and controls is distinct. Finally, we show that human and chimpanzee [CpG](m)-[CA](n) ECE-1c promoter repeats are genetically and functionally distinct. Our data indicate that a short genomic repeat structure constitutes a novel core promoter element, coincides with human evolution, and contributes to the pathogenesis of AD.

Topics

• impedance spectroscopy
• laser emission spectroscopy