Amyloid-b inhibits no-cgmp signaling in a cd36- and cd47-dependent manner

Abstract

Amyloid-b 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-b shares this inhibitory activity. Amyloid-b 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-b. Functional interaction of amyloid-b 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-b were active. In contrast, amyloid-b did not compete with the known ligand SIRPa for binding to CD47. However, both receptors were necessary for amyloid-b to inhibit cGMP accumulation. These data suggest that amyloid-b 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-b can contribute to the nitric oxide signaling deficiencies associated with Alzheimer's disease.