Abstract

(from the application): Alzheimer's Disease ( AD) is characterized by the formation of amyloid plaques and cerebrovascular amyloid deposits, the principal component of which is the ~ 4 kDa amyloid peptide (ABeta). ABeta is derived from a large transmembrane precursor, the amyloid precursor protein (APP), the physiological function of which remains to be elucidated. In the previous 4 years, we have focused on studies of proteins that interact with the C-terminal domain of APP (APPc), and on the phosphorylation of APP. These studies have identified the adaptor protein, FE65, as an important regulator of APP localization and processing. We have also identified Cdk5 as a major kinase responsible for phosphorylation of APPc in neurons, and found that phosphorylation of APP by Cdk5 regulates neurite outgrowth in model neuronal cell lines. The Long-term objectives of this part of the Program Project application are to continue to analyze the regulation of APP by its interaction with the adaptor protein, FE65, and via phosphorylation by Cdk5.
Specific aims of the project are:
Aim 1. To characterize the interaction between APP and FE65. These studies will examine the influence of FE65 on APP processing, and will examine the localization of APP, FE65 and associated proteins in neurons.
Aim 2. To characterize the phosphorylation of APP by Cdk5. These studies will examine the regulation of Cdk5 activity and phosphorylation of APP in intact neurons, the effects of phosphorylation of Thr668 on APP processing, and the structural consequences of phosphorylation of Thr668.
Aim 3. To characterize the regulation of Cdk5. These studies will examine the phosphorylation and dephosphorylation of the catalytic subunit of Cdk5, the phosphorylation and dephosphorylation of the regulatory, p35 and p25, subunits of Cdk5, and the interaction of p35/p25 with the Cdk5 catalytic subunit. The proposed studies should contribute to a greater understanding of signal transduction mechanisms involved in APP processing and APP function, and the contributions these make to AD.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG009464-11
Application #
6545185
Study Section
Special Emphasis Panel (ZAG1)
Project Start
1991-09-30
Project End
2006-06-30
Budget Start
Budget End
Support Year
11
Fiscal Year
2001
Total Cost
Indirect Cost

  Institution

Name
Rockefeller University
Department
Type
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

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

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