K. Boland et al., THE SERPIN-ENZYME COMPLEX RECEPTOR RECOGNIZES SOLUBLE, NONTOXIC AMYLOID-BETA PEPTIDE BUT NOT AGGREGATED, CYTOTOXIC AMYLOID-BETA PEPTIDE, The Journal of biological chemistry, 271(30), 1996, pp. 18032-18044
There is now extensive evidence that amyloid-beta peptide is toxic to
neurons and that its cytotoxic effects can be attributed to a domain c
orresponding to amyloid-beta 25-35, GSNKGAIIGLM. We have shown recentl
y that the serine proteinase inhibitor (serpin)-enzyme complex recepto
r (SEC-R), a receptor initially identified for binding of alpha 1-anti
trypsin (alpha 1-AT) and other serine protease inhibitors, also recogn
izes the amyloid-beta 25-35 domain, In fact, by recognizing the amyloi
d-beta 25-35 domain, SEC-R mediates cell surface binding, internalizat
ion, and degradation of soluble amyloid-beta peptide, In this study, w
e examined the possibility that SEC-R mediates the neurotoxic effect o
f amyloid-beta peptide, A series of peptides based on the sequences of
amyloid-beta peptide and alpha 1-AT was prepared soluble in dimethyl
sulfoxide or insoluble in water and examined in assays for SEC-R bindi
ng, for cytotoxicity in neuronal PC12 cells and murine cortical neuron
s in primary culture, and for aggregation in sodium dodecyl sulfate-po
lyacrylamide gel electrophoresis (SDS-PAGE) analysis, The results show
that amyloid-beta peptide 25-35 and amyloid-a peptide 1-40 prepared s
oluble in dimethyl sulfoxide compete for binding to SEC-R, are nontoxi
c, and migrate as monomers in SDS-PAGE analysis, In contrast, the same
peptides aged in water did not compete for binding to SEC-R but were
toxic and migrated as aggregates in SDS-PAGE, An all-D-amyloid-beta 25
-35 peptide was not recognized at all by SEC-R but retained full toxic
/aggregating properties, Using a series of deleted, substituted, and c
himeric am beta/alpha 1-AT peptides, toxicity correlated well with agg
regation but poorly with SEC-R recognition, In a subclone of PC12 cell
s which developed resistance to the toxic effect of aggregated amyloid
-beta 25-35 there was a 2.53 fold increase in the number of SEC-R mole
cules/cell compared with the parent PC12 cell line, These data show th
at SEC-R does not mediate the cytotoxic effect of aggregated amyloid-b
eta peptide, Rather, SEC-R could play a protective role by mediating c
learance and catabolism of soluble, monomeric amyloid-beta peptide, if
soluble amyloid-beta peptide proves to be an in vivo precursor of the
insoluble, toxic peptide.