M. Tolar, M.A. Marques, J.A.K. Harmony and K.A. Crutcher,
Neurotoxicity of the 22 kDa thrombin-cleavage fragment of apolipoprotein
E and related synthetic peptides is receptor-mediated, J. Neurosci.,
17:5678-5686 (1997).
Abstract
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.
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