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Comparative transcriptome profiling of amyloid precursor protein family members in the adult cortex

Aydin, Dorothee ; Filippov, Mikhail A. ; Tschäpe, Jakob-Andreas ; Gretz, Norbert ; Prinz, Marco ; Eils, Roland ; Brors, Benedikt ; Müller, Ulrike C.

In: BMC Genomics, 12 (2011), Nr. 160. pp. 1-17. ISSN 1471-2164

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Download (865kB) | Lizenz: Creative Commons LizenzvertragComparative transcriptome profiling of amyloid precursor protein family members in the adult cortex by Aydin, Dorothee ; Filippov, Mikhail A. ; Tschäpe, Jakob-Andreas ; Gretz, Norbert ; Prinz, Marco ; Eils, Roland ; Brors, Benedikt ; Müller, Ulrike C. underlies the terms of Creative Commons Attribution 3.0 Germany

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Abstract

Background: The β-amyloid precursor protein (APP) and the related β-amyloid precursor-like proteins (APLPs) undergo complex proteolytic processing giving rise to several fragments. Whereas it is well established that Aβ accumulation is a central trigger for Alzheimer's disease, the physiological role of APP family members and their diverse proteolytic products is still largely unknown. The secreted APPsα ectodomain has been shown to be involved in neuroprotection and synaptic plasticity. The γ-secretase-generated APP intracellular domain (AICD) functions as a transcriptional regulator in heterologous reporter assays although its role for endogenous gene regulation has remained controversial. Results: To gain further insight into the molecular changes associated with knockout phenotypes and to elucidate the physiological functions of APP family members including their proposed role as transcriptional regulators, we performed DNA microarray transcriptome profiling of prefrontal cortex of adult wild-type (WT), APP knockout (APP-/-), APLP2 knockout (APLP2-/-) and APPsα knockin mice (APPα/α) expressing solely the secreted APPsα ectodomain. Biological pathways affected by the lack of APP family members included neurogenesis, transcription, and kinase activity. Comparative analysis of transcriptome changes between mutant and wild-type mice, followed by qPCR validation, identified co-regulated gene sets. Interestingly, these included heat shock proteins and plasticity-related genes that were both down-regulated in knockout cortices. In contrast, we failed to detect significant differences in expression of previously proposed AICD target genes including Bace1, Kai1, Gsk3b, p53, Tip60, and Vglut2. Only Egfr was slightly up-regulated in APLP2-/- mice. Comparison of APP-/- and APPα/α with wild-type mice revealed a high proportion of co-regulated genes indicating an important role of the C-terminus for cellular signaling. Finally, comparison of APLP2-/- on different genetic backgrounds revealed that background-related transcriptome changes may dominate over changes due to the knockout of a single gene. Conclusion: Shared transcriptome profiles corroborated closely related physiological functions of APP family members in the adult central nervous system. As expression of proposed AICD target genes was not altered in adult cortex, this may indicate that these genes are not affected by lack of APP under resting conditions or only in a small subset of cells.

Item Type: Article
Journal or Publication Title: BMC Genomics
Volume: 12
Number: 160
Publisher: BioMed Central; Springer
Place of Publication: London; Berlin; Heidelberg
Date Deposited: 05 Dec 2016 13:35
Date: 2011
ISSN: 1471-2164
Page Range: pp. 1-17
Faculties / Institutes: The Faculty of Bio Sciences > Institute of Pharmacy and Molecular Biotechnology
Medizinische Fakultät Mannheim > Zentrum für Medizinische Forschung
Service facilities > Bioquant
Service facilities > German Cancer Research Center (DKFZ)
Subjects: 570 Life sciences
610 Medical sciences Medicine
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