Annemarie Svane Aavild Poulsen

Regulation of sorLA in general and in Alzheimer's disease

Research output: Contribution to conferencePosterResearchpeer-review

Background: The Sortillin-related receptor (sorLA) is involved in cellular trafficking and processing of the Amyloid precursor protein (APP). A decrease in sorLA expression has been identified in brain tissue from patients suffering from Alzheimer's disease (AD), suggesting that sorLA may be a key regulator of Aß production and that sorLA activity protects against AD. Furthermore, association between Single Nucleotide Polymorphisms (SNPs) from the gene encoding sorLA (gene name: SORL1) and AD was recently identified; suggesting that transcription of SORL1 could be linked to the development of AD. The mechanism behind the regulation of SORL1 expression in general and how AD-associated SNPs influence sorLA levels during AD, has not yet been characterized. Methods: To identify cis - and trans -regulatory factors important for the expression of sorLA, we studied the proximal promoter of SORL1 using in silico analysis and generated promoter constructs for Dual Luciferase Assay. We precipitated proteins from nuclear cell extracts binding to the SORL1 promoter using Streptavidin magnetic beads and biotinylated oligomers. By introduction of constructs for over expression and siRNA molecules for under expression of transcription factors, we determined their effects on sorLA expression by qPCR and Western blotting. Using site-directed mutagenesis we mapped regulatory cis-element binding sites for verified transcription factors. Results: We have identified regions in the SORL1 promoter, important for induction as well as repression of sorLA expression. We identified several trans cription factors that is directly involved in the regulation of sorLA expression, and mapped their binding sites within the proximal SORL1 promoter. Finally, we determined the level of these transcription factors in brain tissue from patients with Alzheimer's disease. Conclusions: We have investigated the regulation of sorLA expression and identified several cis - and trans -regulatory elements important for the proper expression of sorLA. These studies may help to elucidate the mechanisms underlying the observ ed down regulation of sorLA and the linkage to disease onset of SORL1 SNPs in AD patients.
Original languageEnglish
Publication year16 Jul 2014
Publication statusPublished - 16 Jul 2014
EventAlzheimer`s Association International Conference - Copenhagen, Denmark
Duration: 13 Jul 201417 Jul 2014

Conference

ConferenceAlzheimer`s Association International Conference
CountryDenmark
CityCopenhagen
Period13/07/201417/07/2014

    Research areas

  • functional assay,molecular biology

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