Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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A γ-secretase inhibitor blocks Notch signaling in vivo and causes a severe neurogenic phenotype in zebrafish

EMBO Rep 3(7): 688-94

Authors/Editors: Geling A
Steiner H
Willem M
Bally-Cuif L
Haass C
Publication Date: 2002
Type of Publication: Journal Article

Inhibition of amyloid β-peptide (Aβ) production by blocking γ-secretase activity is at present one of the most promising therapeutic strategies to slow progression of Alzheimer's disease pathology. γ-Secretase inhibitors apparently block Aβ generation via interference with presenilin (PS) function. Besides being an essential component of the γ-secretase complex, PS itself may be an aspartyl protease with γ-secretase activity, which is not only required for Aβ production but also for a similar proteolytic process involved in Notch signaling. Here we demonstrate 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. This indicates severe side-effects of γ-secretase inhibitors in any Notch-dependent cell fate decision and demonstrates that the zebrafish is an ideal vertebrate system to validate compounds that selectively affect Aβ production, but not Notch signaling, under in vivo conditions.

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