Premium
P2‐333: The gamma‐secretase modulator CHF5074 acutely reduces brain Aβ42 in the guinea pig model of human β‐amyloid production
Author(s) -
Imbimbo Bruno P.,
Hutter-Paier Birgit,
Cenacchi Valentina,
Volta Roberta,
Villetti Gino,
Windisch Manfred
Publication year - 2008
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.2008.05.1410
Subject(s) - guinea pig , gamma secretase , in vivo , pharmacology , in vitro , amyloid (mycology) , chemistry , human brain , amyloid precursor protein secretase , medicine , amyloid precursor protein , biochemistry , biology , pathology , alzheimer's disease , microbiology and biotechnology , disease , psychiatry
acutely reduce A 40 levels in plasma. However, due to the fundamental role -secretase plays in the intramembrane proteolysis of a number of other proteins, the inhibitor approach can be associated with side-effects including Notch-based liabilities. More recently, modulation of -secretase cleavage of APP has been reported as exemplified by the NSAIDs. This approach is more favourable as modulators cause a shift in cleavage from the amyloidogenic A 42 site towards the less amyloidogenic A 37 and A 38 sites, whereas inhibitors abolish cleavage at all -sites . Thus, the modulators decrease neurotoxic A 42 peptide levels in the absence of any detrimental effect on Notch cleavage. Methods: We have profiled a number of -secretase modulators and inhibitors in vitro and in vivo for their effect on A levels. To determine whether an increase in A 38 could be disadvantageous, we investigated the potential neurotoxic effect of A 38 peptide in vitro on rat primary cortical neurons. Results: In SHSY5Y cells expressing APP Swedish variant, -secretase modulators concentration dependently decreased A 42 while concomitantly increasing A 38. Some compounds also lowered A 40 whereas others had no effect. In transgenic mice over-expressing mutant APP and PS-1 transgenes, administration of compounds decreased A 42 in the brain. The latter effect was associated with an increased level of A 38 and consistent with the profile of a modulator. In contrast, -secretase inhibitors decreased A 38, A 40 and A 42 in cells and in transgenic mice, consistent with the profile of an inhbitor. In rat primary cortical neurons, A 42 caused significant cell death whereas A 38 was not neurotoxic. Conclusions: These findings support the development of -secretase modulators for the treatment of AD.