Chronic Treatment with the -Secretase Inhibitor LY-411,575 Inhibits -Amyloid Peptide Production and Alters Lymphopoiesis and Intestinal Cell Differentiation*

Inhibition of -secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic -amyloid (A ) peptides, is an attractive approach to the treatment of Alzheimer disease. In addition to APP, however, several other -secretase substrates have been identified (e.g. Notch), and altered processing of these substrates by -secretase inhibitors could lead to unintended biological consequences. To study the in vivo consequences of -secretase inhibition, the -secretase inhibitor LY411,575 was administered to C57BL/6 and TgCRND8 APP transgenic mice for 15 days. Although most tissues were unaffected, doses of LY-411,575 that inhibited A production had marked effects on lymphocyte development and on the intestine. LY-411,575 decreased overall thymic cellularity and impaired intrathymic differentiation at the CD4 CD8 CD44 CD25 precursor stage. No effects on peripheral T cell populations were noted following LY-411,575 treatment, but evidence for the altered maturation of peripheral B cells was observed. In the intestine, LY-411,575 treatment increased goblet cell number and drastically altered tissue morphology. These effects of LY-411,575 were not seen in mice that were administered LY-D, a diastereoisomer of LY411,575, which is a very weak -secretase inhibitor. These studies show that inhibition of -secretase has the expected benefit of reducing A in a murine model of Alzheimer disease but has potentially undesirable biological effects as well, most likely because of the inhibition of Notch processing.