Alpha2-macroglobulin
associates with beta-amyloid peptide and prevents fibril formation.
Hughes SR, Khorkova O, Goyal S,
Knaeblein J, Heroux J, Riedel NG, Sahasrabudhe S.
Alpha2-macroglobulin associates with beta-amyloid peptide and
prevents fibril formation. Proc Natl Acad Sci U S A. 1998 Mar
17;95(6):3275-80.
We have used the yeast two-hybrid system to isolate cDNAs encoding
proteins that specifically interact with the 42-aa beta-amyloid
peptide (Abeta), a major constituent of senile plaques in Alzheimer's
disease. The carboxy terminus ofalpha2-macroglobulin (alpha2M), a
proteinase inhibitor released in response to inflammatory stimuli,
was identified as a strong and specific interactor of Abeta,
utilizing this system. Direct evidence for this interaction was
obtained by co-immuno precipitation of alpha2M with Abeta from the
yeast cell, and by formation of SDS-resistant Abeta complexes in
polyacrylamide gels by using synthetic Abeta and purified alpha2M.
The association of Abeta with alpha2M andvarious purified amyloid
binding proteins was assessed by employing a method measuring
protein-protein interactions in liquid phase. The dissociation
constantby this technique for the alpha2M-Abeta association using
labeled purified proteins was measured (Kd = 350 nM). Electron
microscopy showed that a 1:8 ratio of alpha2M to Abeta prevented
fibril formation in solution; the same ratio to Abeta of another
acute phase protein, alpha1-antichymotrypsin, was not active in
preventing fibril formation in vitro. These results were
corroborated by data obtained from an in vitro aggregation assay
employing Thioflavine T. The interaction of alpha2M with Abeta
suggests new pathway(s) for the clearance of the soluble amyloid
peptide.
PMID: 9501253 [PubMed - indexed for MEDLINE]
