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)-r elated synthetic peptides and the 22 kDa N-terminal thrombin-cleavage fragment of apoE. Furthermore, the E4 isoform of the 22 kDa fragment i s significantly more toxic than the same fragment derived from the E3 isoform, suggesting The possibility of a direct role of apoE-associate d neurotoxicity in the pathophysiology of Alzheimer's disease, In the present study, the potential role of cell surface receptors in mediati ng neurotoxicity was assessed by using a variety of agents that should block the heparin-binding and receptor-binding activity of apoE, Effe ctive inhibitors of neurotoxicity of both the apoE peptides and the ap oE fragment include heparin, heparan sulfate, sodium chlorate and hepa rinase, the low-density lipoprotein (LDL) receptor-related protein rec eptor-associated protein, and a polyclonal anti-LDL receptor-related p rotein antibody. These results suggest that tile neurotoxicity of the 22 kDa thrombin cleavage fragment of apoE and related peptides is rece ptor-mediated, and that the most likely candidate receptor is a hepara n sulfate proteoglycan-LDL receptor-related protein complex.