Generation, Metabolism, and Biological Function of Acid

Christian Haass, PhD
Adolf Butenandt Institute (Munich, Germany)
Year Awarded:
2002
Grant Duration:
April 1, 2002 to March 31, 2004
Disease:
Alzheimer's Disease
Award Amount:
$200,000
Grant Reference ID:
A2002008
Award Type:
Standard
Award Region:
International

Generation, Metabolism, and Biological Function of Acid

Details


Presenilin (PS) supports the Intramembraneous cleavage of several substrates, including Notch I-IV and the ß-amyloid precursor protein (ßAPP). In the case of Notch, the PS-supported cleavage results in the production of the Notch intracellular domain (NICD), which is required for signal transduction and the regulation of target gene transcription. In recent work, Dr. Haas and his colleagues identified the corresponding fragment of ßAPP called the amyloid precursor protein intracellular domain (AICD) and found that it is generated by a molecular mechanism that is very similar to NCID. He is now investigating the molecular mechanisms of AICD generation and analyzing the putative similarities of AICD and NICD generation as well as the influence of familial Alzheimer's disease-related mutations on the production of these two cytoplasmic fragments. It is hoped that the expression of the recombinant fragment in tissue culture cells under conditions where its degradation is blocked will help identify genes that are involved. Based on the phenotype obtained from Caenorhabditis elegans (a worm) and zebrafish, conclusions regarding the target genes can be made and genetic modifiers can be isolated. If successful, this project will not only help to identify a biological function of ßAPP but is also important for the development of therapies to block the generation of amyloid -peptide using gamma-secretase inhibitors.

Publications

Okochi M, Steiner H, Fukumori A, Tanii H, Tomita T, Tanaka T, Iwatsubo T, Kudo T, Takeda M, Haass C. Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1. EMBO J. 2002 Oct 15;21(20):5408-16. PubMed Central PMCID: PMC129073.PubMed  

Lammich S, Okochi M, Takeda M, Kaether C, Capell A, Zimmer AK, Edbauer D, Walter J, Steiner H, Haass C. Presenilin-dependent intramembrane proteolysis of CD44 leads to the liberation of its intracellular domain and the secretion of an Abeta-like peptide. J Biol Chem. 2002 Nov 22;277(47):44754-9. Epub 2002 Sep 9. PubMed  

Moehlmann T, Winkler E, Xia X, Edbauer D, Murrell J, Capell A, Kaether C, Zheng H, Ghetti B, Haass C, Steiner H. Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production. Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):8025-30. Epub 2002 Jun 4. PubMed Central PMCID: PMC123014. PubMed [PMID: 12048239;] [link not available]

Edbauer D, Willem M, Lammich S, Steiner H, Haass C. Insulin-degrading enzyme rapidly removes the beta-amyloid precursor protein intracellular domain (AICD). J Biol Chem. 2002 Apr 19;277(16):13389-93. Epub 2002 Jan 23. PubMed  

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