γ-Secretase inhibitors repress thymocyte development
Brandon Hadland,Nancy R. Manley,Dong-Ming Su,Gregory D. Longmore,Chad L. Moore,Michael S. Wolfe,Michael S. Wolfe,Eric H. Schroeter,Raphael Kopan +8 more
TLDR
It is shown that application of γ-secretase inhibitors to fetal thymus organ cultures interferes with T cell development in a manner consistent with loss or reduction of Notch1 function, and this system presents a system in which rapid evaluation of ιsecretase-targeted pharmaceuticals for their ability to inhibit Notch activity can be performed in a relevant context.Abstract:
A major therapeutic target in the search for a cure to the devastating Alzheimer9s disease is γ-secretase. This activity resides in a multiprotein enzyme complex responsible for the generation of Aβ42 peptides, precipitates of which are thought to cause the disease. γ-Secretase is also a critical component of the Notch signal transduction pathway; Notch signals regulate development and differentiation of adult self-renewing cells. This has led to the hypothesis that therapeutic inhibition of γ-secretase may interfere with Notch-related processes in adults, most alarmingly in hematopoiesis. Here, we show that application of γ-secretase inhibitors to fetal thymus organ cultures interferes with T cell development in a manner consistent with loss or reduction of Notch1 function. Progression from an immature CD4 − /CD8 − state to an intermediate CD4 + /CD8 + double-positive state was repressed. Furthermore, treatment beginning later at the double-positive stage specifically inhibited CD8 + single-positive maturation but did not affect CD4 + single-positive cells. These results demonstrate that pharmacological γ-secretase inhibition recapitulates Notch1 loss in a vertebrate tissue and present a system in which rapid evaluation of γ-secretase-targeted pharmaceuticals for their ability to inhibit Notch activity can be performed in a relevant context.read more
Citations
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A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity
Sascha Weggen,Jason L. Eriksen,Pritam Das,Sarah A. Sagi,Rong Wang,Claus U. Pietrzik,Kirk A. Findlay,Tawnya E. Smith,Michael P. Murphy,Thomas Bulter,David E. Kang,Numa R. Marquez-Sterling,Todd E. Golde,Edward H. Koo +13 more
TL;DR: It is reported that the NSAIDs ibuprofen, indomethacin and sulindac sulphide preferentially decrease the highly amyloidogenic Aβ42 peptide (the 42-residue isoform of the amyloids-β peptide) produced from a variety of cultured cells by as much as 80%.
Journal ArticleDOI
Chronic Treatment with the γ-Secretase Inhibitor LY-411,575 Inhibits β-Amyloid Peptide Production and Alters Lymphopoiesis and Intestinal Cell Differentiation
Gwendolyn T. Wong,Denise Manfra,Frederique M. Poulet,Qi Zhang,Hubert B. Josien,Thomas A. Bara,Laura W. Engstrom,Maria Pinzon-Ortiz,Jay S. Fine,Hu-Jung J. Lee,Lili Zhang,Guy A. Higgins,Eric M. Parker +12 more
TL;DR: In vivo studies show that inhibition of γ-secretase has the expected benefit of reducing Aβ in a murine model of Alzheimer disease but has potentially undesirable biological effects as well, most likely because of the inhibition of Notch processing.
Journal ArticleDOI
Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision
Hua Han,Kenji Tanigaki,Norio Yamamoto,Kazuki Kuroda,Momoko Yoshimoto,Tatsutoshi Nakahata,Koichi Ikuta,Tasuku Honjo +7 more
TL;DR: It is suggested that RBP-J, probably by mediating Notch signaling, controls T versus B cell fate decision in lymphoid progenitors.
Journal ArticleDOI
A γ-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish
TL;DR: It is demonstrated that treatment of zebrafish embryos with a known γ‐secretase inhibitor affects embryonic development in a manner indistinguishable from Notch signaling deficiencies at morphological, molecular and biochemical levels, which indicates severe side‐effects of γ-secretase inhibitors in any Notch‐dependent cell fate decision and demonstrates that the zebra fish is an ideal vertebrate system to validate compounds that selectively affect Aβ production, but not Notch signalling, under in vivo conditions.
Journal ArticleDOI
γ-Secretase, notch, Aβ and alzheimer's disease: Where do the presenilins fit in?
TL;DR: Although some data support the idea that the presenilins are in fact the active site of γ-secretase, other data indicate that they might have a more indirect role — for example, in transporting substrates to the correct subcellular compartments for ιsecretase cleavage.
References
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Journal ArticleDOI
Notch Signaling: Cell Fate Control and Signal Integration in Development
TL;DR: Notch signaling defines an evolutionarily ancient cell interaction mechanism, which plays a fundamental role in metazoan development, providing a general developmental tool to influence organ formation and morphogenesis.
Journal ArticleDOI
A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.
Bart De Strooper,Wim Annaert,Philippe Cupers,Paul Saftig,Katleen Craessaerts,Jeff S. Mumm,Eric H. Schroeter,Vincent Schrijvers,Michael S. Wolfe,William J. Ray,Alison Goate,Raphael Kopan +11 more
TL;DR: It is reported that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1.
Journal ArticleDOI
Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.
TL;DR: It is shown that signalling by a constitutively active membrane-bound Notch-1 protein requires the proteolytic release of the Notch intracellular domain (NICD), which interacts preferentially with CSL.
Journal ArticleDOI
Deficient T cell fate specification in mice with an induced inactivation of Notch1.
Freddy Radtke,Anne Wilson,G. Stark,Michelle Bauer,Joost P. M. van Meerwijk,H. Robson MacDonald,Michel Aguet +6 more
TL;DR: It is suggested that Notch1 plays an obligatory and selective role in T cell lineage induction in mice with a neonatally induced loss of Notch 1 function.
Journal ArticleDOI
Notch1 expression in early lymphopoiesis influences B versus T lineage determination.
John C. Pui,David Allman,Lanwei Xu,Susan DeRocco,Fredrick G. Karnell,Sonia Bakkour,Julia Y Lee,Tom Kadesch,Richard R. Hardy,Jon C. Aster,Warren S. Pear +10 more
TL;DR: The results suggest that Notch1 provides a key regulatory signal in determining T lymphoid versus B lymphoid lineage decisions, possibly by influencing lineage commitment from a common lymphoid progenitor cell.