The HHQK domain of β-amyloid provides a structural basis for the immunopathology of Alzheimer's disease

Dana Giulian, Lanny J. Haverkamp, Jiahan Yu, William Karshin, Donald Tom, Jun Li, Anna Kazanskaia, Joel Kirkpatrick, Alex E. Roher

Research output: Contribution to journalArticlepeer-review

Abstract

The β-amyloid peptide 1-42 (Aβ1-42), a major component of neuritic and core plaques found in Alzheimer's disease, activates microglia to kill neurons. Selective modifications of amino acids near the N terminus of Aβ showed that residues 13-16, the HHQK domain, bind to microglial cells. This same cluster of basic amino acids is also known as a domain with high binding affinity for heparan sulfate. Both Aβ binding to microglia and Aβ induction of microglial killing of neurons were sensitive to heparitinase cleavage and to competition with heparan sulfate, suggesting membrane-associated heparan sulfate mediated plaque-microglia interactions through the HHQK domain. Importantly, small peptides containing HHQK inhibited Aβ1-42 cell binding as well as plaque induction of neurotoxicity in human microglia. In vivo experiments confirmed that the HHQK peptide reduces rat brain inflammation elicited after infusion of Aβ 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.

Original languageEnglish (US)
Pages (from-to)29719-29726
Number of pages8
JournalJournal of Biological Chemistry
Volume273
Issue number45
DOIs
StatePublished - Nov 6 1998

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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