Abstract
Inhibition of gamma-secretase, one of the enzymes responsible for the cleavage of the amyloid precursor protein (APP) to produce the pathogenic beta-amyloid (Abeta) peptides, is an attractive approach to the treatment of Alzheimer disease. In addition to APP, however, several other gamma-secretase substrates have been identified (e.g. Notch), and altered processing of these substrates by gamma-secretase inhibitors could lead to unintended biological consequences. To study the in vivo consequences of gamma-secretase inhibition, the gamma-secretase inhibitor LY-411,575 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 Abeta 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 LY-411,575, which is a very weak gamma-secretase inhibitor. These studies show that inhibition of gamma-secretase has the expected benefit of reducing Abeta in a murine model of Alzheimer disease but has potentially undesirable biological effects as well, most likely because of the inhibition of Notch processing.
Highlights
(APP) to produce the pathogenic -amyloid (A) pep- these neuropathological lesions probably contribute to progrestides, is an attractive approach to the treatment of Alzheimer disease
The A peptides are produced by the sequential proteolytic cleavage of the amyloid precursor protein (APP) by - and ␥-secretase. ␥-Secretase is a complex composed of at least four proteins, namely presenilins, nicastrin, PEN-2, and APH-1 [8]
The different in vivo activities of LY-411,575 and LY-D are not because of different pharmacokinetic properties, because the two compounds achieved similar plasma levels after oral administration. These in vitro and in vivo data demonstrate that LY-411,575 and LY-D are excellent tools to distinguish the mechanism-based effects of ␥-secretase inhibition from the compound-related effects that are not due to ␥-secretase inhibition
Summary
(APP) to produce the pathogenic -amyloid (A) pep- these neuropathological lesions probably contribute to progrestides, is an attractive approach to the treatment of Alzheimer disease. 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. These data suggest that in addition to their potential therapeutic benefit in AD, ␥-secretase inhibitors may have liabilities because of inhibition of the proteolytic processing of Notch (and other signaling molecules) that are critical for a variety of cellular functions.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
