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Journal of Neuroscience, Vol 14, 5461-5470, Copyright © 1994 by Society for Neuroscience
Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension
LW Jin, H Ninomiya, JM Roch, D Schubert, E Masliah, DA Otero and T Saitoh
Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla 92093-0624.
Amyloid beta/A4 protein precursor (APP) is secreted into medium by most
cultured cells and can function as an autocrine factor. To study the
biological function of secreted forms of APP (sAPP) on neurons, we used a
clonal CNS neuronal line, B103, which does not synthesize detectable levels
of APP. B103 cells transfected with APP construct developed neurites faster
than the parent B103 cells when plated in a serum-free defined medium.
Neurite outgrowth of B103 cells was promoted by the conditioned medium of
APP-695-over-producing cells or by the bacteria- produced sAPP-695 (named
KB75). A series of peptides having sequences between Ala-319 and Met-335 of
APP-695 also stimulated neurite outgrowth of B103 cells. The sequence of
five amino acids, RERMS (APP 328-332), within this stretch of sequence, was
the shortest active peptide, although the concentration required for the
neuritotropic activity was higher than that of KB75. Binding assay using
125I-labeled APP 17-mer peptide corresponding to Ala-319 to Met-335 of
APP-695 as a ligand demonstrated specific and saturable cell-surface
binding sites. The predicted KD value was 20 +/- 5 nM and the Bmax value
was 80 +/- 8 fmol/10(6) cells. The binding could be displaced with KB75. A
17-mer peptide with reverse sequence neither induced neurite outgrowth nor
competed for the binding. A bacteria-produced sAPP fragment lacking the
active 17-mer sequence (named KB75 delta) did not compete with 125I-
labeled 17-mer for binding or stimulate neurite extension. A peptide of
sequence RMSQ (APP 330-333), which partially overlaps the active sequence
RERMS, could block the neuritotropic effects of both KB75 and the 17-mer at
higher concentrations. APP 17-mer was also found to induce the accumulation
of inositol polyphosphates, suggesting that the APP 17-mer effects involve
activation of inositol phospholipid signal transduction systems. These data
indicate that sAPP induces neurite extension through cell-surface binding
and that the domain containing the RERMS sequence (APP 328-332) represents
the active site responsible for this function.
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