Alzheimer's Plaque Depresses eNOS Production

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.

From press release:

A researcher at the University of Pittsburgh School of Medicine, in collaboration with scientists from the National Institutes of Health (NIH), has discovered that the deadly plaques of Alzheimer's disease interact with certain cellular proteins to inhibit normal signals that maintain blood flow to the brain. Their findings, which could lead to new approaches to treat the dementia, were recently published in Public Library of Science One.

Levels of nitric oxide (NO) -- a signaling molecule that helps regulate blood flow, immune and neurological processes -- are known to be low in the brains of people who have Alzheimer's disease, but the reason for that hasn't been clear, said study co-author Jeffrey S. Isenberg, M.D., M.P.H., associate professor, Division of Pulmonary, Allergy, and Critical Care Medicine, Pitt School of Medicine.

"Our research sheds light on how that loss of NO might happen, and reveals biochemical pathways that drug discoverers might be able to exploit to find new medicines for Alzheimer's," he said. "There is evidence that suggests enhancing NO levels can protect neurons from degenerating and dying."

The researchers, led by first author Thomas Miller, Ph.D., and senior author David D. Roberts, Ph.D., both of the Laboratory of Pathology in NIH's National Cancer Institute (NCI), found in mouse and human cell experiments that amyloid-beta, the main component of the plaques that accumulate on brain cells in Alzheimer's, binds to a cell surface receptor called CD36, which causes decreased activity of the enzyme soluble guanylate cyclase to reduce NO signaling. But that inhibitory effect required the presence of and interaction with CD47, another cell surface protein, indicating that additional steps in the pathway remain to be identified.

"It's possible that an agent that could block either CD36 or CD47 could slow the progress of neuronal degeneration in Alzheimer's by protecting the production of NO in the brain," Dr. Isenberg said. "Importantly, we have already indentified therapeutic agents that can interrupt the inhibitory signal induced by these interactions to maximize NO production, signaling and sensitivity."

He and his colleagues currently are studying such blockers in a variety of disease models.