The HHQK domain of beta-amyloid provides a structural basis for the immunopathology of Alzheimer's disease.
The beta-amyloid peptide 1-42 (Abeta1-42), 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 Abeta 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 Abeta binding to microglia and Abeta 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 Abeta1-42 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 Abeta 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.
Giulian
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D
Alzheimer's Disease Research Center, Baylor College of Medicine, Houston, Texas 77030, USA. dgiulian@bcm.tmc.edu
Haverkamp
L J
LJ
Yu
J
J
Karshin
W
W
Tom
D
D
Li
J
J
Kazanskaia
A
A
Kirkpatrick
J
J
Roher
A E
AE
D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D006801:Humans; D017628:Microglia / Q000276:immunology / Q000473:pathology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)