Work

α2‐Macroglobulin Complexes with and Mediates the Endocytosis of β‐Amyloid Peptide via Cell Surface Low‐Density Lipoprotein Receptor‐Related Protein

Year: 1997

Type: article

Abstract: A primary histopathological feature of Alzheimer's disease is the accumulation of beta-amyloid (A beta) in the brain of afflicted individuals. However, A beta 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 A beta forms stable complexes with activated alpha2-macroglobulin (alpha2M*), a physiological ligand for the low-density lipoprotein receptor-related protein (LRP) that is abundantly expressed in the CNS. These alpha2M*/125I-A beta complexes are immunoreactive with both anti-A beta and anti-alpha2M IgG and are stable under various pH conditions, sodium dodecyl sulfate, reducing agents, and boiling. We demonstrate that alpha2M*/125I-A beta 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 125I-A beta 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 A beta via a physiological ligand.

Source: Journal of Neurochemistry

DOI: 10.1046/j.1471-4159.1997.69051904.x

Authors: Masaaki Narita, David M. Holtzman, Alan L. Schwartz, Guojun Bu

Institution: Washington University in St. Louis

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: Alzheimer's Association, American Foundation for Aging Research, National Institutes of Health, National Institute on Aging