Absence of endoproteolysis but no effects on amyloid beta production by alternative splicing forms of presenilin-1, which lack exon 8 and replace D257A

It is well known that presenilin-1 (PS1) is involved in cleavage of amyloid precursor protein (APP) at the gamma -secretase site, and that the amino a cids residues of D257 and D385 in PS1 are critical for this cleavage of APP and the endoproteolysis of itself. An alternatively spliced form of PS1 sk ipping exon 8 (PS1d8), which has D257A at the splice junction of exon 7/9, is expressed in human brain and in some cell lines. In this study, we exami ned production of Amyloid beta (A beta) and the endoproteolysis of the holo proteins in PS1d8-expressing neuroblastoma cells. Western blotting showed a n absence of endoproteolysis in PS1d8. However, PS1d8 did not affect the pr oduction of AP, which is different from the artificial point mutant PS 1D25 711. These results suggest that endoproteolysis of PS 1 and gamma -secretas e activity could be independent. (C) 2000 Elsevier Science B.V. All rights reserved.