Alpha2-macroglobulin enhances the clearance of endogenous soluble beta-amyloid peptide via low-density lipoprotein receptor-related protein in cortical neurons.
Apolipoprotein E and alpha2-macroglobulin (alpha2M) are genetic risk factors for late-onset Alzheimer's disease, and both bind a cell surface receptor, the low-density lipoprotein receptor-related protein (LRP). To investigate the role of LRP on preventing the accumulation of beta-amyloid peptide (A beta), we examined the effects of alpha2M on the clearance of endogenous A beta. Studies were performed in primary Tg2576 transgenic mouse cortical neuronal cultures expressing human mutant amyloid precursor protein (APP) 695. This system allowed us to follow endogenous A beta using immunoblots to detect monomeric forms of the peptide. A beta and APP levels were measured in conditioned media. We found that activated alpha2M (alpha2M*) substantially decreased soluble A beta levels and had no effect on secreted or full-length APP levels. Native alpha2M, which is not a ligand for LRP, did not affect A beta levels. The receptor-associated protein, which inhibits interaction of all ligands with LRP in vitro, prevented alpha2M*-induced decreases of soluble A beta levels. These data suggest that alpha2M* affects soluble A beta clearance rather than A beta production. Further studies showed that similar A beta clearance via an LRP-mediated pathway was observed after treatment with another LRP ligand, lactoferrin. Taken together, these data demonstrate that alpha2M* enhances the clearance of soluble A beta via LRP in cortical neurons.
Qiu
Z
Z
Alzheimer Research Unit, Massachusetts General Hospital and Harvard Medical School, Boston 02129, USA.
Strickland
D K
DK
Hyman
B T
BT
Rebeck
G W
GW
D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D004622:Embryo, Mammalian; D005260:Female; D006801:Humans; D007700:Kinetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D000511:alpha-Macroglobulins / Q000494:pharmacology / Q000502:physiology*
D016229:Amyloid beta-Peptides; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; D000511:alpha-Macroglobulins