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P2‐307: A stable G‐quadruplex within the ADAM10 5'‐UTR is involved in translational repression of ADAM10
Author(s) -
Lammich Sven,
Büll Dominik,
Zilow Sonja,
Kamp Frits,
Nuscher Brigitte,
Ludwig AnnKatrin,
Prinzen Claudia,
Fahrenholz Falk,
Haass Christian
Publication year - 2011
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.2011.05.1185
Subject(s) - adam10 , untranslated region , amyloid precursor protein , hek 293 cells , metalloproteinase , chemistry , protein precursor , microbiology and biotechnology , biology , messenger rna , alzheimer's disease , disintegrin , gene , biochemistry , medicine , matrix metalloproteinase , disease , pathology
signs of dementia, apoptosis hallmarks and neurofibrillary tangles (NFT) remains unclear. In the amyloidogenic pathway, beta-APP undergoes betacleavage yielding the membrane-anchored C-terminal stub C99, while in physiological conditions, alpha-secretase cleaves beta-APP to raise themembrane-anchored C-terminal stub C83. Both fragments C99 and C83 behave as gamma-secretase substrate to generate AICD (APP IntraCellular Domain) and A-beta or p3 respectively. Thus both amyloidogenic and non-amyloidogenic pathway should theoretically generated AICD.Methods: In this study, we analyzed, in vitro, the gamma-secretase activity from exogenous substrates (C100 and C84) or cells expressing SPC99 and SPC83. C100 and C84 are recombinant protein corresponding to C99 and C83 fragments respectively. The SPC99 and SPC83 constructions holding the APP signal sequence followed by the C-terminal fragments of APP (C99 or C83) are subcloned in pcDNA3 vector and transfected in HEK293 cells. Results: Using the recombinant substrates, we observed that AICD is predominantly produced from C100 compared to C84. Furthermore, HEK293 cells expressing C99 produce much more AICD compared to cells expressing C83. AICD is predominantly produced from the C99 in the amyloidogenic pathway.