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Volume 17, Number 20, Issue of October 15, 1997 pp. 7714-7724
Copyright ©1997 Society for Neuroscience

Late Compartments of Amyloid Precursor Protein Transport in SY5Y Cells Are Involved in -Amyloid Secretion

Received March 14, 1997; revised July 7, 1997; accepted July 24, 1997.

Gisela C. Peraus¹, Colin L. Masters², and Konrad Beyreuther¹

¹ Center for Molecular Biology Heidelberg, The University of Heidelberg, D-69120 Heidelberg, Germany, and ² Department of Pathology, The University of Melbourne, Parkville, Victoria 3052, Australia

Amyloid plaques, composed mainly of the 39-43 amino acid A4 peptide, are a characteristic feature of Alzheimer's disease. Generation of A4 by proteolytic processing of the amyloid precursor protein (APP) is thought to occur in a pathway that includes the activity of two as yet unknown proteases, with -secretase cleaving at the N terminus and -secretase releasing the C terminus of A4. Inhibition studies and the finding that cell surface APP can serve as a direct precursor of A4 suggest that the endosomal/lysosomal compartment is involved in the proteolysis of APP into A4.

In this study we targeted APP695 chimeric proteins directly into the endosomal/lysosomal compartment. This decreased the amount of released A4, while the generation of the A4 N terminus continued. APP695 proteins were constructed also, which carried sorting signals responsible for recycling between the trans-Golgi network (TGN) and the cell surface. These proteins were processed into secreted A4 at even higher levels than wild-type APP695. Moreover, retention of APP695 proteins in the endoplasmic reticulum led to neither A4 secretion nor to processing by -secretase in human SH-SY5Y neuroblastoma cells.

These data suggest that a -cleavage activity resides in a late endosomal compartment and that a -cleavage occurs in early endosomes, resulting in the generation of A4 peptides with the majority ending at residue 40.

Key words: Alzheimer's disease; APP processing; -amyloid; chimeric proteins; endosomal/lysosomal compartment; transport

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