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α 2 ‐Macroglobulin Complexes with and Mediates the Endocytosis of β‐Amyloid Peptide via Cell Surface Low‐Density Lipoprotein Receptor‐Related Protein
Author(s) -
Narita Masaaki,
Holtzman David M.,
Schwartz Alan L.,
Bu Guojun
Publication year - 1997
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1997.69051904.x
Subject(s) - macroglobulin , ldl receptor , receptor , endocytosis , ligand (biochemistry) , chemistry , lipoprotein , microbiology and biotechnology , peptide , lrp1 , amyloid (mycology) , low density lipoprotein , sodium dodecyl sulfate , biochemistry , biophysics , biology , cholesterol , inorganic chemistry
A primary histopathological feature of Alzheimer's disease is the accumulation of β‐amyloid (Aβ) in the brain of afflicted individuals. However, Aβ is produced continuously as a soluble protein in healthy individuals where it is detected in serum and CSF, suggesting the existence of cellular clearance mechanisms that normally prevent its accumulation and aggregation. Here, we demonstrate that Aβ forms stable complexes with activated α 2 ‐macroglobulin (α 2 M ⋆ ), a physiological ligand for the low‐density lipoprotein receptor‐related protein (LRP) that is abundantly expressed in the CNS. These α 2 M ⋆ / 125 I‐Aβ complexes are immunoreactive with both anti‐Aβ and anti‐α 2 M IgG and are stable under various pH conditions, sodium dodecyl sulfate, reducing agents, and boiling. We demonstrate that α 2 M ⋆ / 125 I‐Aβ complexes can be degraded by glioblastoma cells and fibroblasts via LRP, because degradation is partially inhibited by receptor‐associated protein (RAP), an antagonist of ligand interactions with LRP. In contrast, the degradation of free 125 I‐Aβ is not inhibited by RAP and thus must be mediated via an LRP‐independent pathway. These results suggest that LRP can function as a clearance receptor for Aβ via a physiological ligand.