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P1–410: The intracellular domain of the amyloid–beta precursor protein is not involved in nuclear signaling
Author(s) -
Hebert Sebastien S.,
Serneels Lutgarde,
Craessaerts Katleen,
Derks Carmen,
De Strooper Bart
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.2006.05.789
Subject(s) - amyloid precursor protein , amyloid precursor protein secretase , alpha secretase , microbiology and biotechnology , amyloid beta , biology , intracellular , gamma secretase , gene expression , signal transduction , gene , chemistry , biochemistry , alzheimer's disease , peptide , medicine , disease
Background: The main hallmark of Alzheimer’s disease (AD) is the presence of insoluble amyloid-beta (A-beta) deposits in the brain. A-beta peptides are produced by proteolytic processing of the amyloid-beta precursor protein (APP) by betaand gamma-secretases. Blocking A-beta generation by inhibiting or modulating gamma-secretase processing of APP is an attractive but problematic drug target for the treatment of AD. Apart from side effects caused by interference with the Notch signaling pathway, recent results suggest that blocking gamma-secretase would also interfere with other signaling pathways. Indeed, proteolytic processing of APP by gamma-secretase releases, concomitant with the A-beta peptides, the APP intracellular domain (AICD) which has been proposed to function in gene transcription regulation. Objectives: Several candidate AICD target genes have been identified over the last years including KAI1, APP, GSK3-beta and Neprilysin. Here, we raised the questions whether gamma-secretase inhibition would affect the expression of these putative AICD target genes and whether AICD has indeed a direct role in gene transcription regulation. Methods and Results: We found no effects of gamma-secretase inhibitors on the protein expression levels of these putative AICD target genes in different cell lines. Also deficiencies of different members of the gamma-secretase complex or the APP-family did not consistently affect the expression levels of these candidate AICD target genes in fibroblasts and in vivo. While AICD overexpression could activate weakly different endogenous promoters, the observed activity was at least one order of magnitude lower than the one obtained with the authentic gene transcription activator NICD (the Notch intracellular domain). We finally demonstrate that Fe65, a major AICD binding protein, transactivates a wide variety of different promoters, including the viral SV40 promoter, independently from AICD co-expression. Conclusions: We demonstrate that the selective inhibition of gamma-secretase and A-beta production does not cause major effects on the levels of genes that were suggested to be regulated by AICD. While this work cannot exclude that other yet unidentified genes are controlled by AICD mediated signaling, we dare to conclude that deregulation of the proposed AICD target genes is not a major additional concern when contemplating gamma-secretase inhibitors as a therapy in AD.