THE HHQK DOMAIN OF BETA-AMYLOID PROVIDES A STRUCTURAL BASIS FOR THE IMMUNOPATHOLOGY OF ALZHEIMERS-DISEASE

The beta-amyloid peptide 1-42 (A beta 1-42), a major component of neur itic and core plaques found in Alzheimer's disease, activates microgli a to kill neurons. Selective modifications of amino acids near the N t erminus of A beta showed that residues 13-16, the HHQK domain, bind to microglial cells. This same cluster of basic amino acids is also know n as a domain with high binding affinity for heparan sulfate. Both A b eta binding to microglia and A beta induction of microglial killing of neurons were sensitive to heparitinase cleavage and to competition wi th heparan sulfate, suggesting membrane-associated heparan sulfate med iated plaque-microglia interactions through the HHQK domain, Important ly, small peptides containing HHQK inhibited A beta 1-42 cell binding as well as plaque induction of neurotoxicity in human microglia. In vi vo experiments confirmed that the HHQK peptide reduces rat brain infla mmation elicited after infusion of A beta peptides or implantation of native plaque fragments. Strategies which exploit HHQK-like agents may offer a specific therapy to block plaque-induced microgliosis and, in this way, slow the neuronal loss and dementia of Alzheimer's disease.