MISSENSE MUTATIONS ASSOCIATED WITH FAMILIAL ALZHEIMERS-DISEASE IN SWEDEN LEAD TO THE PRODUCTION OF THE AMYLOID PEPTIDE WITHOUT INTERNALIZATION OF ITS PRECURSOR

Production of soluble amyloid peptide precursor (APP) and amyloid pept ide (A beta) was measured in CHO cells transfected by the wild-type AP P 695 cDNA sequence or by the same sequence carrying missense mutation s associated with familial Alzheimer's disease in Sweden. Deletion of the C-terminal domain of the protein corresponding to residues 654 to 695 of APP695 not only inhibited very significantly the internalizatio n of APP at 37 degrees C, but also led to the secretion of an uncleave d APP in the culture medium of CHO cells. This deletion did not affect A beta production from the Swedish APP but was able to inhibit the pr oduction of the wild-type APP. These results demonstrate that, in CHO cells, the internalization of the wild-type APP is needed for A beta p roduction, while the production of the amyloid peptide from Swedish AP P is independent of the internalization process. (C) 1996 Academic Pre ss, Inc.