A protective role of the low density lipoprotein receptor-related protein against amyloid beta-protein toxicity.
In order to delineate the neuroprotective role of the low density lipoprotein receptor-related protein (LRP) against amyloid beta-protein toxicity, studies were performed in C6 cells challenged with amyloid beta-protein in the presence or absence of activated alpha(2)-macroglobulin. Toxicity was assessed via two cell viability assays. We found that this endocytic receptor conferred protection against amyloid beta-protein toxicity in the presence of activated alpha(2)-macroglobulin and its down-regulation via inhibition by receptor-associated protein or transfection of cells with presenilin 1, increased susceptibility to amyloid beta-protein toxicity. Increased surface LRP immunoreactivity in response to amyloid beta-protein challenge was associated with increased translocation of LRP from the endoplasmic reticulum to the surface, rather than from increased mRNA or protein expression. Furthermore, this translocation of LRP to the surface was mediated by a calcium/calmodulin protein kinase II-dependent signaling pathway. These studies provide evidence for a protective role of LRP against amyloid beta-protein toxicity and may explain the aggressive nature of presenilin-1 mutation in familial Alzheimer's disease.
Van Uden
E
E
Departments of Neurosciences, Medicine, and Pathology, University of California, San Diego, School of Medicine, La Jolla, California 92093-0624, USA.
Sagara
Y
Y
Van Uden
J
J
Orlando
R
R
Mallory
M
M
Rockenstein
E
E
Masliah
E
E
D000544:Alzheimer Disease / Q000209:etiology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D017209:Apoptosis; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004721:Endoplasmic Reticulum; D006801:Humans; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism*; D053764:Presenilin-1; D019704:Protein Disulfide-Isomerases / Q000302:isolation & purification; D011971:Receptors, Immunologic / Q000378:metabolism*; D015854:Up-Regulation; D000511:alpha-Macroglobulins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008565:Membrane Proteins; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1; D011971:Receptors, Immunologic; D000511:alpha-Macroglobulins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019704:Protein Disulfide-Isomerases