alpha2-Macroglobulin as a beta-amyloid peptide-binding plasma protein.
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 an aggregated fibrillar form in both diffuse and senile plaques in the brains of patients 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 major circulating endoproteinase inhibitor, which has recently been shown to be present in senile plaques in AD, binds 125I-A beta(1-42) with high affinity (apparent dissociation constant of 3.8 x 10(-10) M). Approximately 1 mol of A beta is bound per mole of alpha2M. Both native and methylamine-activated alpha2M bind 125I-A beta(1-42). The binding of 125I-A beta(1-42) to alpha2M is enhanced by micromolar concentrations of Zn2+ (but not Ca2+) and is inhibited by noniodinated A beta(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, another plaque-associated protein, inhibits both the binding of 125I-A beta(1-42) to alpha2M as well as the degradation of 125I-A beta(1-42) by proteinase-activated alpha2M. Moreover, the binding of 125I-A beta(1-42) to alpha2M protects the peptide from proteolysis by exogenous trypsin. These data suggest that alpha2M may function as a carrier protein for A beta and could serve to either facilitate or impede clearance of A beta from tissues such as the brain.
Du
Y
Y
Division of CNS Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, U.S.A.
Ni
B
B
Glinn
M
M
Dodel
R C
RC
Bales
K R
KR
Zhang
Z
Z
Hyslop
P A
PA
Paul
S M
SM
D016229:Amyloid beta-Peptides / Q000032:analysis / Q000378:metabolism*; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004586:Electrophoresis; D006801:Humans; D007457:Iodine Radioisotopes; D011233:Precipitin Tests; D012680:Sensitivity and Specificity; D015032:Zinc / Q000494:pharmacology; D000514:alpha 1-Antichymotrypsin / Q000494:pharmacology; D000511:alpha-Macroglobulins / Q000032:analysis / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D007457:Iodine Radioisotopes; D000514:alpha 1-Antichymotrypsin; D000511:alpha-Macroglobulins; D015032:Zinc; D002118:Calcium