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P4‐065: Impact of Apoe Polymorphisms on Amyloid‐Beta Oligomerization and Associated Cognitive Decline
Author(s) -
Fitz Nicholas F.,
Carter Alexis Y.,
Nam Kyong Nyon,
Castranio Emilie L.,
Mounier Anais,
Wolfe Cody M.,
Lefterov Iliya,
Koldamova Radosveta
Publication year - 2016
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.2016.06.2155
Subject(s) - apolipoprotein e , microglia , oligomer , transcriptome , long term potentiation , cognitive decline , amyloid (mycology) , allele , biology , chemistry , microbiology and biotechnology , biophysics , biochemistry , gene , medicine , dementia , disease , immunology , inflammation , gene expression , receptor , botany , organic chemistry
this C-terminal cleavage of APP in vivo by mutating the cleavage site, many mouse AD phenotypes were ameliorated. This work describes our progress toward discovering small molecule inhibitors of this destructive process. Methods: Using the D664 (APP695) cleavage site-specific antibody (APP delta C31, Enzo), we measured the level of N-terminal fragment resulting from this intracellular APP proteolysis. We developed an AlphaLISA assay for library screening purposes and a commercial ELISA for validation and research purposes for this C-terminal cleavage. For our library screening, the cell model system used was CHO cells stably transfected with APP770 (CHO-7W). We stimulated cleavage at the D739 caspase cleavage site (APP770) by treating these cells with cerevastatin and were able to reduce this cleavage and rescue cell death with the pan-caspase inhibitor Q-VD-OPh. An ex vivo I5 (hAPPwt) mouse hippocampal slice culture model was also utilized to validate active compounds. Results: Several classes and individual compounds were found to be effective at reducing C-terminal APP caspase cleavage and rescuing cell death in a dose-dependent manner. The most effective include SERCA inhibitors, inhibitors of Wnt signaling and calcium channel antagonists. Conclusions: We have identified and validated individual and classes of compounds that inhibit C-terminal APP caspase cleavage and rescue cell death in a dose–dependent manner. The resulting N-terminal APP fragment could be an important AD biomarker and blocking this cleavage could prove to be an important AD therapeutic approach.