title: Amyloid-β inhibits No-cGMP signaling in a CD36- and CD47-dependent manner.
abstract: Amyloid-β interacts with two cell surface receptors, CD36 and CD47, through which the matricellular protein thrombospondin-1 inhibits soluble guanylate cyclase activation. Here we examine whether amyloid-β shares this inhibitory activity. Amyloid-β inhibited both drug and nitric oxide-mediated activation of soluble guanylate cyclase in several cell types. Known cGMP-dependent functional responses to nitric oxide in platelets and vascular smooth muscle cells were correspondingly inhibited by amyloid-β. Functional interaction of amyloid-β with the scavenger receptor CD36 was indicated by inhibition of free fatty acid uptake via this receptor. Both soluble oligomer and fibrillar forms of amyloid-β were active. In contrast, amyloid-β did not compete with the known ligand SIRPα for binding to CD47. However, both receptors were necessary for amyloid-β to inhibit cGMP accumulation. These data suggest that amyloid-β interaction with CD36 induces a CD47-dependent signal that inhibits soluble guanylate cyclase activation. Combined with the pleiotropic effects of inhibiting free fatty acid transport via CD36, these data provides a molecular mechanism through which amyloid-β can contribute to the nitric oxide signaling deficiencies associated with Alzheimer's disease.
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Miller
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Isenberg
authors.forename: Hubert B
authors.initials: HB
authors.lastname: Shih
authors.forename: Yichen
authors.initials: Y
authors.lastname: Wang
authors.forename: David D
authors.initials: DD
authors.lastname: Roberts
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000166:cytology; D018955:CD36 Antigens / Q000096:biosynthesis; D051928:CD47 Antigen / Q000096:biosynthesis; D002417:Cattle; D006152:Cyclic GMP / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology; D006801:Humans; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D011487:Protein Conformation; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D013552:Swine; D014471:Umbilical Veins / Q000166:cytology
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D016229:Amyloid beta-Peptides; D018955:CD36 Antigens; D051928:CD47 Antigen; D011720:Pyrazoles; D011725:Pyridines; D009569:Nitric Oxide; D006152:Cyclic GMP