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.
Cellular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037-1099, USA. yliu@salk.edu
Yuanbin
Y
Liu
Richard
R
Dargusch
Cindy
C
Banh
Carol A
CA
Miller
David
D
Schubert
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