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O4‐03–06: Notch or gamma‐secretase‐deficient skin creates an environment inducing a lethal systemic B‐lymphoproliferative disorder by overproducing TSLP, a sentinel for epidermal integrity
Author(s) -
Demehri Shadmehr,
Liu Zhenyi,
Lee Jonghyeob,
Lin Meei-Hua,
Crosby Seth,
Roberts Christopher,
Grigsby Perry,
Miner Jeffrey,
Farr Andrew,
Kopan Raphael
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.523
Subject(s) - notch signaling pathway , thymic stromal lymphopoietin , immunology , biology , haematopoiesis , cancer research , microbiology and biotechnology , signal transduction , atopic dermatitis , stem cell
enzymatic cleavage is performed by an enzyme complex composed of presenilin (PS), nicastrin, Aph-1 and Pen-2. Since -secretase is promiscuous it is a great challenge to inhibit A production while not interfering with other important signalling pathways such as Notch. PS contains the catalytic part of the complex while nicastrin is suggested to have a more receptor-like role. Our group are focused on finding the specificity between different substrates to the PS molecule and to nicastrin. Methods: We are monitoring substrate processing, interaction and complex assembly with luciferase reporter gene assay, ELISA, mass-spectometry and co-immunoprecipitation using PS1 / 2 deficient cell lines and nicastrin -/cells expressing APP or Notch substrates, together with different mutants/deletions and truncations of the PS1 and nicastrin molecules. -Secretase inhibitors and modulators are used to elucidate what domains are involved in compound interactions. Results: Data will be presented that certain domains in the -secretase complex are differentially affecting the APP and Notch processing. Conclusions: Our findings suggest that cleavage of APP and Notch is affected by different domains in the -secretase complex which will open up new interesting possibilities to design new compounds for the treatment of Alzheimer’s disease.