The relative utilization of alternative processing pathways for APP can be regulated by the activation state of certain protein phosphorylation signal transduction pathways. For example, activation of protein kinase C (PKC), or inactivation of protein phosphatases 1 and 2A, leads to a relative increase in utilization of the nonamyloidogenic, """"""""alpha- secretase"""""""" cleavage pathway for APP processing at the expense of other pathways. Current data suggest that major candidate phosphorylation- state sensitive targets relevant to the molecular basis of PKC-activated processing (or """"""""regulated cleavage"""""""") of APP include secretase enzymes and/or other components of the APP trafficking/processing apparatus. Further efforts to distinguish among these possibilities will be investigated during the next award period and are summarized here. One approach will be the in vitro reconstitution in manipulatable systems of certain events relevant to regulated cleavage of APP (Specific Aim I). A porated cell system has been developed that provides for the selective study of APP processing events occurring at the plasma membrane in the absence or presence of cytosolic constitutents; another system that has been developed involves the study of the regulation of formation of nascent constitutive secretory vesicles containing APP. Another approach involves the study of metabolism of APP in Saccharomyces cerevisiae (Specific Aim II). We have demonstrated that alpha-secretase-like events may occur in Saccharomyces, and we now are poised to study how PKC regulates normal and sec mutant constitutive pathways in Saccharomyces. These approaches in in vitro reconstituted systems and Saccharomyces will be complemented by subcellular fractionation studies in control and drug- treated intact mammalian cells (Specific Aim III). Finally, in addition to the foregoing studies which focus primarily on alpha-secretase cleavage of APP, we also propose to study the role of the multivesicular body in the gamma-secretase cleavage of APP which gives rise to the carboxyl-terminus of A/beta and p3 (Specific Aim IV). A clear elucidation of the molecular and cellular basis for these features of APP metabolism could form the basis of a rational therapeutic strategy for diminishing the cerebral amyloid deposition which accompanies Alzheimer's disease.

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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
Xu, Jian; Kurup, Pradeep; Nairn, Angus C et al. (2012) Striatal-enriched protein tyrosine phosphatase in Alzheimer's disease. Adv Pharmacol 64:303-25

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