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Does Neuroglobin Play a Role in Alzheimer's Disease?

By Michael S. Rafii, MD, PhD
Director, Memory Disorders Clinic
Associate Medical Director, Alzheimer's Disease
Cooperative Study
University of California San Diego

Neuroglobin is a protein that was first identified in 2000. It is a member of the globin family, similar to hemoglobin (which carries oxygen inside red blood cells) and myoglobin (which carries oxygen inside muscle cells). It is a highly conserved protein, meaning that it is a very important protein in all species, ranging from mice to humans. It is known to be activated by cerebral ischemia (decreased brain oxygen) and is known to protect neurons from such injury.

Despite its ability to bind to oxygen, like hemoglobin and myoglobin, neuroglobin is unlikely to function as an oxygen delivery system. Instead, it seems to be involved in scavenging reactive oxygen molecules (oxidants) generated in response to brain ischemia and injury. Many researchers believe antioxidants are beneficial in various neurodegenerative diseases.

Recent work had shown that neuroglobin decreases beta amyloid neurotoxicity in animal models of AD. Now, a paper from a group at the Johns Hopkins University (Szymanski et al, Neurobiology of Aging, 2009), shows that variations in the gene for the neuroglobin protein, may in fact increase one's risk of developing AD, by producing inefficient neuroglobin. This inefficient protein is unable to defend against the toxicity of beta amyloid.

Adding to a growing body of evidence about the importance of this protein for the health of the aging brain, the researchers canvassed the genetic neighborhood of neuroglobin and, for the first time in a human population, linked variations with a risk for Alzheimer's. The team has found that individuals with genetic variations equating to less neuroglobin production have an increased risk for Alzheimer's.

The scientists found that neuroglobin levels decreased with advancing age, which, is consistent with risk of Alzheimer's increasing with advancing age. They also found that levels of neuroglobin were lower in women than in men, which is consistent with the fact that women have a slightly higher risk of Alzheimer's. About two times as many patients in the general population with Alzheimer's are women which, in part, can be attributed to the fact that women live longer and therefore have more of a chance of getting Alzheimer's. Having corrected for that disparity, researchers have noted a slightly higher risk in women than in men.

The researchers were surprised to find that neuroglobin levels were higher in the brain tissue from Alzheimer's patients than that of the control group. Counter-intuitive though it seemed at first, it actually makes sense, especially in light of previously published studies that indicated a protective function for neuroglobin and showed that mouse brains respond to stress - in this case, a lack of oxygen - by producing more neuroglobin.

The scientists think that neuroglobin production is increased as reaction to the insult of the Alzheimer's disease. But in certain individuals with the less effective genetic form of neuroglobin, it's simply not enough of a protective response to effectively defend the brain.

More work will be needed to determine if neuroglobin can be affected in a positive way to reduce beta amyloid toxicity in AD patients, and if genetic testing for variations of the gene for neuroglobin may aid in the diagnosis of AD.