STEROID-HORMONES BLOCK AMYLOID FIBRIL-INDUCED (4,5-DIMETHYLTHIAZOL-2-YL)-2,5-DIPHENYLTETRAZOLIUM BROMIDE (MTT) FORMAZAN EXOCYTOSIS - RELATIONSHIP TO NEUROTOXICITY

Perhaps the most reproducible early event induced by the interaction o f amyloid beta peptide (A beta) with the cell is the inhibition of cel lular 3-(4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (M TT) reduction, We recently demonstrated that cytotoxic amyloid peptide s such as A beta and human amylin inhibit cellular MTT reduction by dr amatically enhancing MTT formazan exocytosis, We now show the followin g: (a) Insulin and glucagon, when converted to fibrils with beta-pleat ed sheet structure, induce MTT formazan exocytosis that is indistingui shable from that induced by A beta, NAC35, an amyloidogenic fragment o f alpha-synuclein (or NACP), also induces MTT formazan exocytosis, (b) All protein fibrils with the beta-pleated sheet structure examined ar e toxic to rat hippocampal neurons. (c) Many sterol sex hormones (e.g. , estradiol and progesterone) block amyloid fibril-enhanced MTT formaz an exocytosis as well as MTT formazan exocytosis in control cells by a cting at a common late step in the exocytic pathway. Steroids fail, ho wever, to protect hippocampal neurons from acute amyloid fibril toxici ty. These findings suggest that the ability to enhance MTT formazan ex ocytosis and to induce neurotoxicity are common biological activities of protein fibrils with beta-pleated sheet structure but that enhanced MTT formazan exocytosis is not sufficient for acute A beta neurotoxic ity.