The identification of compounds that selectively reduce the amount of amyloidogenic Aβ42 peptide may provide the basis for the development of pharmacological treatments for Alzheimer's disease. In the accompanying posters (Eriksen, J. et. al., and Weggen, S. et. al., SFN abstracts, 2001), we described agents that selectively reduce the levels of Aβ42 in medium from a variety of cell lines and from brains of APP transgenic mice. To understand the action of this class of compounds, we investigated their effect on various Aβ species by performing MALDI-TOF and bicine-urea gel analyses on conditioned medium from cells cultured with these compounds. Surprisingly, we found that the selective reduction in Aβ42 is accompanied by an increase in Aβ38, while levels of Aβ40 as well as other shorter Aβ peptides (Aβ34, Aβ37, and Aβ39) remained relatively constant. We are currently investigating if this shift can be induced in vivo and if other agents have similar activity. To our knowledge this is the first time chemica...