Detecting bioactive amyloid beta peptide species in Alzheimer's disease.
Amyloid beta peptide (A beta) is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the form of A beta that induces neurodegeneration in AD, defined here as bioactive A beta, is not clear. Preventing the formation of bioactive A beta or inactivating previously formed bioactive A beta should be a promising approach to treat AD. We have previously developed a cell-based assay for the detection of bioactive A beta species. The assay is based upon the correlation between the ability of an A beta sample to induce a unique form of cellular MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] formazan exocytosis, and its ability to activate glia and induce neurotoxicity. Here, we show that this cell-based assay is not only useful for a cellular model of A beta amyloidogenesis but is also able to detect bioactive A beta species in a transgenic mouse model of AD, as well as in post-mortem cortex samples from AD patients. There is a good correlation between the extent of glia activation and the level of bioactive A beta species in the mouse brain. A promising deuteroporphyrin that can inactivate bioactive A beta species was also identified using this assay. These novel insights and findings should have important implications for the treatment of AD.
Liu
Yuanbin
Y
Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037-1099, USA. yliu@salk.edu
Dargusch
Richard
R
Banh
Cindy
C
Miller
Carol A
CA
Schubert
David
D
D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000096:biosynthesis; D016229:Amyloid beta-Peptides / Q000032:analysis* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D001923:Brain Chemistry; D002478:Cells, Cultured; D003905:Deuteroporphyrins / Q000494:pharmacology; D004195:Disease Models, Animal; D005089:Exocytosis / Q000187:drug effects; D005260:Female; D005562:Formazans / Q000378:metabolism* / Q000493:pharmacokinetics*; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012680:Sensitivity and Specificity; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism; D013778:Tetrazolium Salts / Q000378:metabolism* / Q000493:pharmacokinetics*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D003905:Deuteroporphyrins; D005562:Formazans; D010446:Peptide Fragments; D013778:Tetrazolium Salts; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C079782:MTT formazan