alpha2-Macroglobulin as a beta-amyloid peptide-binding
plasma protein.
Du Y, Ni B, Glinn M, Dodel RC, Bales
KR, Zhang Z, Hyslop PA, Paul SM. alpha2-Macroglobulin as a beta-amyloid
peptide-binding plasma protein. 1: J Neurochem. 1997
Jul;69(1):299-305.Division of CNS Research, Lilly Research
Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285,
U.S.A.
The beta-amyloid peptide (A beta) is a normal proteolytic processing
product of the amyloid precursor protein, which is constitutively
expressed by many, if not most, cells. For reasons that are still
unclear, A beta is deposited in anaggregated fibrillar form in both
diffuse and senile plaques in the brains ofpatients with Alzheimer's
disease (AD). The factor(s) responsible for the clearance of soluble
A beta from biological fluids or tissues are poorly understood. We
now report that human alpha2-macroglobulin (alpha2M), a
majorcirculating endoproteinase inhibitor, which has recently been
shown to be presentin senile plaques in AD, binds 125I-A beta(1-42)
with high affinity (apparentdissociation constant of 3.8 x 10(-10)
M). Approximately 1 mol of A beta is boundper mole of alpha2M. Both
native and methylamine-activated alpha2M bind 125I-Abeta(1-42). The
binding of 125I-A beta(1-42) to alpha2M is enhanced by
micromolarconcentrations of Zn2+ (but not Ca2+) and is inhibited by
noniodinated Abeta(1-42) and A beta(1-40) but not by the reverse
peptide A beta(40-1) or the cytokines interleukin 1beta or
interleukin 2. alpha1-Antichymotrypsin, anotherplaque-associated
protein, inhibits both the binding of 125I-A beta(1-42) toalpha2M as
well as the degradation of 125I-A beta(1-42) by
proteinase-activatedalpha2M. Moreover, the binding of 125I-A
beta(1-42) to alpha2M protects the peptide from proteolysis by
exogenous trypsin. These data suggest that alpha2Mmay function as a
carrier protein for A beta and could serve to either facilitateor
impede clearance of A beta from tissues such as the brain.
PMID: 9202323 [PubMed - indexed for MEDLINE]
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