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J Biol Chem, Vol. 274, Issue 45, 32295-32300, November 5, 1999

Expression of -Amyloid Precursor Protein-CD3 Chimeras to Demonstrate the Selective Generation of Amyloid _1-40 and Amyloid _1-42 Peptides within Secretory and Endocytic Compartments

Salvador Soriano, Abraham S. C. Chyung^§, Xiaohua Chen, Gorazd B. Stokin, Virginia M.-Y. Lee^§, and Edward H. Koo

From the  Department of Neurosciences 0691, University of California, San Diego, La Jolla, California 92093-0691 and the ^§ Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Amyloid -protein (A) is the main constituent of amyloid fibrils found in senile plaques and cerebral vessels in Alzheimer's disease (AD) and is derived by proteolysis from the -amyloid precursor protein (APP). We have analyzed the amyloidogenic processing of APP using chimeric proteins stably transfected in Chinese hamster ovary cells. The extracellular and transmembrane domains of APP were fused to the cytoplasmic region derived from the CD3  chain of the T cell antigen receptor (CD3). CD3 contains an endoplasmic reticulum (ER) retention motif (RKK), in the absence of which the protein is targeted to lysosomes without going through the cell surface (Letourneur, F., and Klausner, R.D. (1992) Cell 69, 1143-1157). We used the wild-type sequence of CD3 to create an APP chimera predicted to remain in the ER (APP_ER). Deletion of the RKK motif at the C terminus directed the protein directly to the lysosomes (APP_LYS). A third chimera was created by removing both lysosomal targeting signals in addition to RKK (APP). This last construct does not contain known targeting signals and consequently accumulates at the cell surface. We show by immunofluorescence and by biochemical methods that all three APP chimeras localize to the predicted compartments within the cell, thus providing a useful model to study the processing of APP. We found that A_1-40 is generated in the early secretory and endocytic pathways, whereas A_1-42 is made mainly in the secretory pathway. More importantly, we provide evidence that, unlike in neuronal models, both ER/intermediate compartment- and endocytic-derived A forms can enter the secretable pool. Finally, we directly demonstrate that lysosomal processing is not involved in the generation or secretion of either A_1-40 or A_1-42.

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