Journal of Alzheimer’s Disease 31 (2012) 793–800 DOI 10.3233/JAD-2012-120472 IOS Press 793 Direct Downregulation of CNTNAP2 by STOX1A is Associated with Alzheimer’s Disease Daan van Abel a , Omar Michel a , Rob Veerhuis b , Marlies Jacobs c , Marie van Dijk a and Cees B.M. Oudejans a,∗ a Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands b The Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands c Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands Accepted 9 May 2012 Abstract. STOX1A is a transcription factor which is functionally and structurally similar to the forkhead box protein family. STOX1A has been shown to be associated with pre-eclampsia, a pregnancy associated disease, and to have potential implications in late onset Alzheimer’s disease. However, the exact function of STOX1A and its target genes are still largely unknown. Therefore, in this study we performed chromatin immunoprecipitation coupled to shotgun cloning to discover novel STOX1A target genes. Our results show that CNTNAP2, a member of the neurexin family, is directly downregulated by STOX1A. Additionally, we show that CNTNAP2 expression is downregulated in the hippocampus of Alzheimer’s disease patients where STOX1A expression has been shown to be upregulated. In conclusion, these results further indicate the potential involvement of STOX1A and its target genes in the etiology of Alzheimer’s disease. Keywords: Alzheimer’s disease, CNTNAP2, FOXP2, myelination, STOX1A Supplementary data available online: http://www.j-alz.com/issues/31/vol31-4.html#supplementarydata04 INTRODUCTION Forkhead box proteins, characterized by a DNA binding motif termed the winged helix domain [1], are a family of transcription factors that play a role in the regulation of genes involved in multiple disease associ- ated pathways [2]. Previously, we found that Storkhead box 1 (STOX1), a transcription factor structurally and functionally related to the forkhead box protein family, is a susceptibility gene for pre-eclampsia, a hyperten- sive disorder of pregnancy [3]. In addition to STOX1 as a pre-eclampsia susceptibility gene, a recent study per- formed in our lab showed that STOX1, which resides ∗ Correspondence to: Cees B.M. Oudejans, Department of Clini- cal Chemistry, VU University Medical Center, De Boelelaan 1117, HV Amsterdam 1081, The Netherlands. Fax: +31 20 444 3865; E-mail: cbm.oudejans@vumc.nl. on chromosome 10q22, is also functionally important in late onset Alzheimer’s disease (LOAD) [4]. LOAD is a disease with progressive and insidious neurode- generation of the central nervous system resulting in memory loss and impairments in behavior, language, and visual-spatial skills in elderly patients (>65 years of age) [5]. Interestingly, while both syndromes (pre-eclampsia and LOAD) lack shared clinical features, both share multiple susceptibility loci which exceed the thresh- old for significant linkage found on chromosomes 2, 9, 10, and 12 [7–14]. Furthermore, these loci are situ- ated at positions near or at 2p12, 2p25, 9p13, 10q22, and 12q22 for which at least 10q22 is subject to a parent-of-origin effect with maternal segregation in both syndromes [9, 15]. These (epi)genetic similari- ties let us to suggest that these chromosomal regions ISSN 1387-2877/12/$27.50 © 2012 – IOS Press and the authors. All rights reserved