Aug. 15, 2005 Scientists at the University of Rochester Medical Center have discovered a link between a prominent developmental gene and neurovascular dysfunction in Alzheimer's disease.
The gene plays a major role in the growth and remodeling of vascular systems. But, in brain cells of people with Alzheimer's disease, expression of the gene is low, the scientists found, revealing a new piece of the Alzheimer's puzzle.
In laboratory studies, the scientists also showed that restoration of the gene expression level in the human brain cells stimulated the formation of new blood vessels. It also increased the level of a protein that removes amyloid beta peptide, the toxin that builds up in brain tissue in Alzheimer's disease.
In further studies, the scientists, led by Berislav Zlokovic, M.D., Ph.D., deleted one copy of the gene in mice, creating echoes of the damage of Alzheimer's, including reduced ability to grow blood vessels in the brain and impaired clearance of amyloid beta.
"This is a new pathway for the study and treatment of Alzheimer's disease," said Zlokovic. "This gene could be a therapeutic target. If we can stop this cycle, we could slow or stop the progression of the neuronal component of this disease."
An article by Zlokovic and his team detailing the research findings appears Sunday Aug. 14 in the online version of Nature Medicine. The article will be published in the September print edition of Nature Medicine.
Zlokovic is a professor in the University of Rochester Medical Center's Department of Neurosurgery and director of the Frank P. Smith Laboratories for Neuroscience and Neurosurgical Research.
The gene targeted in the research is a homeobox gene known as MEOX2 and also as GAX. A homeobox gene encodes proteins that determine development. Zlokovic calls it a "big boss."
The scientists studied human brain endothelial cells taken from autopsy samples from people with Alzheimer's. They found that expression of MEOX2, or mesenchyme homeobox 2, is low in the cells of those with Alzheimer's.
"The cells with low levels can't form any kind of vascular system or any kind of network," Zlokovic said. "They just start dying."
In restoring expression of the gene, the Rochester scientists showed for the first time that it suppresses a specific transcription factor. When the expression of MEOX2 is low, the factor "rampages" and allows apoptosis or programmed cell death in the brain vascular system, Zlokovic said.
When MEOX2 expression is low, the research also showed that a protein that helps with the clearance of amyloid beta is suppressed.
Zlokovic views the findings reported in Nature Medicine as support for his belief that Alzheimer's is a neurovascular disease.
"If you find a problem in the brain, it doesn't necessarily mean that it started in the brain," he said. "It's not that neuronal injury is not important. It's that other things are more important."
But Zlokovic said that it is not clear yet whether the low expression of the gene results in the death of brain cells and Alzheimer's disease or that the disease in neurons results in the low expression of the disease.
"But if we can restore the dysfunctional gene, we might be able to slow or stop the disease wherever it started," Zlokovic said.
The National Institutes of Health provided some of the funding for the research.
In November 2004, Zlokovic received a MERIT award from the National Institute on Aging. The award, worth approximately $5 million in funding, will be used to further his research for new ways to treat or prevent Alzheimer's disease. Zlokovic was selected by his peers at NIH to receive the award based on the consistent high quality of his work and leadership and commitment in the field over several years.
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