Neurotoxicity of the 22 kDa thrombin-cleavage fragment of apolipoprotein E and related synthetic peptides is receptor-mediated.
Potent neurotoxicity is associated with both apolipoprotein E (apoE)-related synthetic peptides and the 22 kDa N-terminal thrombin-cleavage fragment of apoE. Furthermore, the E4 isoform of the 22 kDa fragment is significantly more toxic than the same fragment derived from the E3 isoform, suggesting the possibility of a direct role of apoE-associated neurotoxicity in the pathophysiology of Alzheimer's disease. In the present study, the potential role of cell surface receptors in mediating neurotoxicity was assessed by using a variety of agents that should block the heparin-binding and receptor-binding activity of apoE. Effective inhibitors of neurotoxicity of both the apoE peptides and the apoE fragment include heparin, heparan sulfate, sodium chlorate and heparinase, the low-density lipoprotein (LDL) receptor-related protein receptor-associated protein, and a polyclonal anti-LDL receptor-related protein antibody. These results suggest that the neurotoxicity of the 22 kDa thrombin cleavage fragment of apoE and related peptides is receptor-mediated, and that the most likely candidate receptor is a heparan sulfate proteoglycan-LDL receptor-related protein complex.
Tolar
M
M
Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Marques
M A
MA
Harmony
J A
JA
Crutcher
K A
KA
D000818:Animals; D001057:Apolipoproteins E / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured / Q000187:drug effects; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D006497:Heparan Sulfate / Q000633:toxicity*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D018110:Receptors, Lipoprotein / Q000187:drug effects*; D013917:Thrombin / Q000494:pharmacology
D001057:Apolipoproteins E; D006497:Heparan Sulfate; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D018110:Receptors, Lipoprotein; D013917:Thrombin