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P4–270: Treatments with an amyloid–binding D–amino acid peptide affect amyloid deposition in APP/PS1 mutant mice
Author(s) -
Groen Thomas,
Kadish Inga,
Wyss James M.,
Wiesehan Katja,
Willbold Dieter
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.2006.05.2009
Subject(s) - fibrillogenesis , peptide , mutant , genetically modified mouse , p3 peptide , chemistry , amyloid (mycology) , amino acid , amyloid precursor protein , fibril , biochemistry , microbiology and biotechnology , medicine , endocrinology , transgene , alzheimer's disease , biology , inorganic chemistry , disease , gene
tions in CHO cells. Objective(s): Here we propose a different mechanism of action for T0901317 independent of LXR receptor activation and lipid metabolism. Results: We show that T0901317 inhibits Abeta production in a cell free in vitro assay of gamma-secretase activity in a dose dependent manner. Furthermore, in H4 cells, stably overexpressing human APP, we are able to demonstrate a dose dependent reduction of Abeta 38 which parallels a dose dependent increase of Abeta 42. At concentrations higher then 10 M we also see a slight decrease of Abeta 40 which is most likely due to unspecific inhibitory or toxic effects since viability of the cells is impaired. This pattern on Abeta 38, Abeta 40 and Abeta 42 is similar to the inverse action of certain non-steroidal anti-inflammatory drugs (NSAIDs) which are believed to be direct modifiers of the gamma-secretase proteolytic complex. Indeed we can show that addition of T0901317 is able to compete with the Abeta 42 lowering effect of a typical NSAIDs on APP processing. Thus we suggest that T090317 is binding to the same site as the g-secretase modulators belonging to the structurally related NSAID compound class. The concentration of T0901317 required for modification of APP cleavage is about 100-fold higher than the published IC50 value for the LXR receptor. Conclusions: In summary, our data strongly suggest an “off target” effect of the LXR agonist T0901317 on the gamma-secretase complex.