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P1–359: Identification of genes that regulate the processing of the β–amyloid precursor protein and are candidates for association with late–onset Alzheimer's disease by a genome–wide siRNA screen
Author(s) -
Stone David,
Majercak John,
Ray Jim,
Espeseth Amy,
Shi Xiao-Ping,
Simon Adam,
Marine Shane,
Stec Erica,
Ferrer Marc,
Bartz Steven,
Gates Adam,
Wolffe Carrie,
Shughrue Paul,
Burchard Julja,
Beher Dirk,
Rosahl Thomas,
Koblan Ken,
Strulovici Berta,
Hazuda Daria,
Shearman Mark,
Sachs Alan,
Seabrook Guy
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.737
Subject(s) - small interfering rna , gene , biology , amyloid precursor protein , hek 293 cells , transfection , transgene , amyloid precursor protein secretase , secretion , alzheimer's disease , microbiology and biotechnology , genetics , biochemistry , disease , medicine
Although dysregulation of cholesterol balance may be related to the onset of neurological disease, the molecular mechanisms that underlie the brainspecific expression of the human CYP46 (hCYP46) have never been described. Objective(s): The human CYP46 5’-flanking region has been cloned in order to identify cis-regulatory elements involved in the brainspecific expression of this gene. Methods: PCR was used to amplify the human CYP46A1 genomic fragment. Several promoter deletion reporter vectors were used in transfection/transactivation studies. Results: Like many neuronal genes, the hCYP46 5’ upstream region is GC-rich and lacks a consensus TATA box. Transfection-transactivation studies using hCYP46 reporter gene constructs have allowed us to identify the presence of a CCAAT/Enhancer Binding Proteins (C/EBPs) responsive region in the proximal promoter. Electrophoretic mobility shift assays, have shown that the C/EBP-responsive elements do not correspond to the canonical C/EBP binding site. Cross-talk with the multiple SP-1 binding sites was assessed. Conclusions: Several recent studies in mammals show that C/EBP mRNA is widely expressed in adult mouse brain and that this protein could be implicated in long-term synaptic plasticity and memory consolidation in rat hippocampus. Interestingly, significant increases in the C/EBP expression levels have been shown in AD compared to non-demented cortex. The identification of C/EBP responsive region involved the CYP46 brainspecific expression, may therefore contribute to novel approaches to the characterization of endogenous regulatory circuits that control pathophysiological situations.