Alzheimer's disease (AD) is characterized by the formation of amyloid plaques and cerebrovascular amyloid deposits, the principal component of which is about 4kDa amyloid peptide (A/beta). Alpha/beta is derived from a large transmembrane precursor, the amyloid precursor protein (APP), the physiological function of which remains to be elucidated. Thus, the long-term objectives of this part of the Program Project application are to identify the biochemical properties of APP. A complete understanding of the function of APP will be important in understanding the processes involved in amyloidogenesis and the contribution that alterations in the normal functions of APP may play in AD. Specific objectives include:
(Aims I and II) The structure, cellular distribution and metabolism of APP suggest that the protein may play a role in one or more aspects of cellular signalling. The cytoplasmic domain is conserved in each APP isoform, indicating an important function for this region of the protein. Proteins which interact with this domain will be purified using biochemical and molecular biological techniques and characterized using biochemical, immunological and structural methods, including cloning of the cDNAs for the protein(s);
Aim III) The short intracellular domain of APP appears to have no enzymatic activity. Therefore, the phosphorylation of APP is likely to regulate the interaction of the intracellular domain with one or more binding proteins. The effects of phosphorylation on the interaction of APP with identified binding proteins will be examined;
(Aim I V) Previous studies have shown that the COOH-terminal domain of APP is involved in certain aspects of APP trafficking and metabolism. We will examine the effect of the interaction of APP binding proteins on APP processing in cell models.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG009464-07
Application #
6234256
Study Section
Project Start
1997-09-30
Project End
1998-06-30
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Type
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Bettayeb, Karima; Hooli, Basaraj V; Parrado, Antonio R et al. (2016) Relevance of the COPI complex for Alzheimer's disease progression in vivo. Proc Natl Acad Sci U S A 113:5418-23
Bettayeb, Karima; Chang, Jerry C; Luo, Wenjie et al. (2016) ?-COP modulates A? peptide formation via retrograde trafficking of APP. Proc Natl Acad Sci U S A 113:5412-7
Liebmann, Thomas; Renier, Nicolas; Bettayeb, Karima et al. (2016) Three-Dimensional Study of Alzheimer's Disease Hallmarks Using the iDISCO Clearing Method. Cell Rep 16:1138-1152
Ceglia, Ilaria; Reitz, Christiane; Gresack, Jodi et al. (2015) APP intracellular domain-WAVE1 pathway reduces amyloid-? production. Nat Med 21:1054-9
Tian, Yuan; Chang, Jerry C; Greengard, Paul et al. (2014) The convergence of endosomal and autophagosomal pathways: implications for APP-CTF degradation. Autophagy 10:694-6
Chiba, Kyoko; Araseki, Masahiko; Nozawa, Keisuke et al. (2014) Quantitative analysis of APP axonal transport in neurons: role of JIP1 in enhanced APP anterograde transport. Mol Biol Cell 25:3569-80
Hochard, Arnaud; Oumata, Nassima; Bettayeb, Karima et al. (2013) Aftins increase amyloid-?42, lower amyloid-?38, and do not alter amyloid-?40 extracellular production in vitro: toward a chemical model of Alzheimer's disease? J Alzheimers Dis 35:107-20
Tian, Yuan; Chang, Jerry C; Fan, Emily Y et al. (2013) Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer's APP-CTF for terminal degradation via autophagy. Proc Natl Acad Sci U S A 110:17071-6
Oh, Yong-Seok; Gao, Pu; Lee, Ko-Woon et al. (2013) SMARCA3, a chromatin-remodeling factor, is required for p11-dependent antidepressant action. Cell 152:831-43
Bettayeb, Karima; Oumata, Nassima; Zhang, Yuanyuan et al. (2012) Small-molecule inducers of Aýý-42 peptide production share a common mechanism of action. FASEB J 26:5115-23

Showing the most recent 10 out of 115 publications