Detecting bioactive amyloid β peptide species in Alzheimer's disease

Amyloid beta peptide (Abeta) is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the form of Abeta that induces neurodegeneration in AD, defined here as bioactive Abeta, is not clear. Preventing the formation of bioactive Abeta or inactivating previously formed bioactive Abeta should be a promising approach to treat AD. We have previously developed a cell-based assay for the detection of bioactive Abeta species. The assay is based upon the correlation between the ability of an Abeta 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 Abeta amyloidogenesis but is also able to detect bioactive Abeta 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 Abeta species in the mouse brain. A promising deuteroporphyrin that can inactivate bioactive Abeta species was also identified using this assay. These novel insights and findings should have important implications for the treatment of AD.