Scientists at the University of Rochester Medical Center havediscovered a link between a prominent developmental gene andneurovascular dysfunction in Alzheimer's disease.
The gene plays a major role in the growth and remodeling of vascularsystems. But, in brain cells of people with Alzheimer's disease,expression of the gene is low, the scientists found, revealing a newpiece of the Alzheimer's puzzle.
In laboratory studies, the scientists also showed thatrestoration of the gene expression level in the human brain cellsstimulated the formation of new blood vessels. It also increased thelevel of a protein that removes amyloid beta peptide, the toxin thatbuilds 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 thedamage of Alzheimer's, including reduced ability to grow blood vesselsin the brain and impaired clearance of amyloid beta.
"This is a new pathway for the study and treatment of Alzheimer'sdisease," said Zlokovic. "This gene could be a therapeutic target. Ifwe can stop this cycle, we could slow or stop the progression of theneuronal component of this disease."
An article by Zlokovic and his team detailing the research findingsappears Sunday Aug. 14 in the online version of Nature Medicine. Thearticle will be published in the September print edition of NatureMedicine.
Zlokovic is a professor in the University of Rochester Medical Center'sDepartment of Neurosurgery and director of the Frank P. SmithLaboratories for Neuroscience and Neurosurgical Research.
The gene targeted in the research is a homeobox gene known as MEOX2 andalso as GAX. A homeobox gene encodes proteins that determinedevelopment. Zlokovic calls it a "big boss."
The scientists studied human brain endothelial cells taken from autopsysamples from people with Alzheimer's. They found that expression ofMEOX2, or mesenchyme homeobox 2, is low in the cells of those withAlzheimer's.
"The cells with low levels can't form any kind of vascular system orany kind of network," Zlokovic said. "They just start dying."
In restoring expression of the gene, the Rochester scientists showedfor the first time that it suppresses a specific transcription factor.When the expression of MEOX2 is low, the factor "rampages" and allowsapoptosis or programmed cell death in the brain vascular system,Zlokovic said.
When MEOX2 expression is low, the research also showed that a proteinthat 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 meanthat it started in the brain," he said. "It's not that neuronal injuryis not important. It's that other things are more important."
But Zlokovic said that it is not clear yet whether the low expressionof the gene results in the death of brain cells and Alzheimer's diseaseor that the disease in neurons results in the low expression of thedisease.
"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 NationalInstitute on Aging. The award, worth approximately $5 million infunding, will be used to further his research for new ways to treat orprevent Alzheimer's disease. Zlokovic was selected by his peers at NIHto receive the award based on the consistent high quality of his workand leadership and commitment in the field over several years.
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