DEFECTIVE NEURITE EXTENSION IS CAUSED BY A MUTATION IN AMYLOID BETA A4 (A-BETA) PROTEIN-PRECURSOR FOUND IN FAMILIAL ALZHEIMERS-DISEASE/

Clonal central nervous system neuronal cells, B103, do not synthesize detectable endogenous APP or APLP. B103 cells transfected with both wi ld-type (B103/APP) and mutant APP construct (B103/APP Delta NL) secret ed comparable amounts of soluble forms of APP (sAPP). B103/APP cells p roduced sAPP and cleaved at amyloid beta/A4 (A beta) 16, the alpha-sec retase site, and B103/APP Delta NL cells produced sAPP beta cleaved at A beta 1, the beta-secretase site. B103/APP Delta NL cells developed fewer neurites than B103/APP cells in a serum-free defined medium. Neu rite numbers of parent B103 cells were increased by the 50% conditione d medium (CM) from B103/APP cells but reduced by the CM from B103/APP Delta NL cells. Chemically synthesized A beta at concentration levels higher than 1 nM reduced numbers of neurites from B103 or B103/APP Del ta NL cells. However, A beta at 1-100 nM could not reduce the neurite number of B103/APP cells. The protective activity against A beta's del eterious effect to reduce neurite numbers was attributed to sAPP alpha in the CM. Although sAPP alpha could block the effect of A beta, sAPP beta could not do so under the identical condition, suggesting the im portance of the C-terminal 15-amino acid sequence in sAPP alpha. Never theless, sAPP alpha's protective activity required the N-terminal sequ ence around RERMS, previously identified to be the active domain of sA PP beta. The overall effect of APP mutation which overproduced A beta and sAPP beta and underproduced sAPP alpha was a marked decline in the neurotrophic effect of APP. We suggest that the disruption of balance between the detrimental effect of A beta and the trophic effect of sA PP may be important in the pathogenesis of AD caused by this pathogeni c APP mutation. (C) 1997 John Wiley & Sons, Inc.