Medical Device Daily

A paper in the Jan. 16, 2007 issue of the Proceedings of the National Academy of Sciences casts Alzheimer’s disease against type: as a cardiovascular disorder at its root.

Reduced blood flow is a well-known symptom of Alzheimer’s disease, but that is viewed as an effect of the disorder. Senior author Berislav Zlokovic described the prevailing opinion as “well, the brain is atrophying because of the disease, so not as much blood as usual is needed.”

But he believes that the opposite cause and effect relationship is true: “the brain [may be] dying because of the reduced blood flow.”

The scientists studied the role of two cardiovascular proteins, serum response factor or SRF, and myocardin, which are the chief regulators of arterial contraction. The scientists found that both are overexpressed in tissues from patients with late-stage Alzheimer’s disease.

“We don’t know exactly why,” Zlokovic told Medical Device Daily’s sister publication, BioWorld Today, adding that hypoxia or a genetic polymorphism are just two possibilities. But the result is clear: “Blood flow regulation is disrupted.”

And that disruption, in turn, may be a contributing factor in the dementia that makes Alzheimer’s so devastating. “Normally, with attention there is an increase in blood flow to parts of the brain,” Zlokovic explained. But with high levels of myocardin and SRF, blood vessels are no longer able to dilate to accommodate blood flow. And this state of affairs “doesn’t support brain function.”

The work was done by Zlokovic, a professor of neurological surgery, and his colleagues from biotech startup Socratech Research Laboratories (Rochester, New York), the University of Rochester Medical School (also Rochester) and the State University of New York at Stony Brook. They first did tissue studies and found that both myocardin and SRF genes are more highly expressed in vascular smooth muscle cells from the brains of Alzheimer’s patients than in control brains, and that such high expression led to arterial wall muscles contracting more than usual.

The scientists next did in vivo studies — a somewhat challenging task in this case. Knockouts lacking either gene never make it past early embryonic development, since they have severe cardiac abnormalities, and overexpressing the Srf gene is lethal for the same reason.

Zlokovic and his colleagues got around this by delivering genes to the brain surface via a cranial window, which, as Zlokovic explained, is “not gene transfer to the brain itself” but targets the blood vessels on the brain surface. Using this technique they found that when either gene was expressed more strongly than usual, blood flow in the brain was reduced, much like it is in Alzheimer’s disease in people. Conversely, when they used short hairpin RNAs to silence SRF, the phenomenon was reversed, and blood flow increased.

Exposing cells to A-beta peptides, which form amyloid plaques, did not lead to increased expression of serum response factor, suggesting that increases in blood vessel contractility cause the protein accumulations, rather than the other way around.

The technology has been licensed to Socratech, a spinout from the University of Rochester where Zlokovic is chief scientific officer. The company, which Zlokovic said has identified gene targets and is currently doing high-throughput screening to find molecules that are active against those targets, is focused on new treatments for Alzheimer’s and stroke.