LA JOLLA, Calif. , August 15, 2007
A prominent problem in AIDS is a form of dementia that robs one’s ability to concentrate and perform normal movements. Scientists at the Burnham Institute for Medical Research (Burnham) have discovered how HIV/AIDS disrupts the normal replication of stem cells in the adult brain, preventing new nerve cells from forming. Drs. Stuart Lipton, Marcus Kaul, Shu-ichi Okamoto and their colleagues uncovered a novel molecular mechanism that inhibits stem cell proliferation and that could possibly be triggered in other neurodegenerative diseases as well. These findings were made available to medical researchers today through priority publication online by the journal Cell Stem Cell
A normally functioning adult human brain has the ability to partially replenish or repair itself through neurogenesis, the proliferation and development of adult neural progenitor/stem cells (aNPCs) into new nerve cells. Neurogenesis can take place only within specific regions of the brain, such as the dentate gyrus of the hippocampus.
The hippocampus is the brain’s central processing unit, critical to learning and memory. aNPCs differentiate, adapt, and assimilate into existing neural circuits and mature with guidance from neurotransmitters, the chemical substances that nerve cells use to communicate with one another. The brain’s self-renewal through neurogenesis is impaired in AIDS dementia, Alzheimer’s, Huntington’s, and other neurodegenerative diseases, as evidenced by a greatly reduced number of aNPCs in brain tissue from individuals suffering from these diseases.
The Burnham team focused on the determining the effect of a protein associated with AIDS, called HIV/gp120, which plays a key role in the pathogenesis of AIDS dementia.
In initial work with cell cultures in Petri dishes, the researchers methodically ruled out the possibility that HIV/gp120 would be inducing the death of stem cells and determined instead that HIV/gp120 was acting by inhibiting stem cell proliferation. Next, they confirmed these results in a special mouse strain bred to express HIV/gp120 in its brain. This mouse model for AIDS dementia mimics several features of the disease process found in humans. They observed a significant decrease in the number of proliferating stem cells in the brains of HIV/gp120-mice compared with similar tissue from normal, wild-type mice.
HIV/gp120 is known to interact with two receptors, called chemokine receptors, which are expressed on aNPCs. The researchers discovered that the same two receptors were targeted by HIV/gp120 sourced from either mouse or human brain tissue.
In search of a mechanism behind the finding that HIV/gp120 reduced proliferation of aNPCs, the scientists studied the effect of the protein on the cell cycle. Cells undergo seasons or cycles, known as G1, S, G2, and M (for mitosis, or cell division). They found that cells exposed to HIV/gp120 got stuck in the G1 or resting phase, and that the cell cycle was arrested.
Cell cycle is studied intensively by cancer researchers who have delineated certain “checkpoint” pathways that can jam cell proliferation, one of the key behaviors of cancer. Checkpoint pathways are overcome by cancers when they fool the body’s normal machinery into producing more cancerous cells. With dementia, it turns out that the opposite is true: the Burnham team discovered that HIV/AIDS could co-opt the checkpoint pathway to prevent stem cells in the brain from dividing and multiplying.
One such checkpoint pathway is modulated by an enzyme called p38 mitogen-activated protein kinase (MAPK), whose activity is known to disrupt the cell cycle. In mature nerve cells, the Burnham team had previously shown that HIV/gp120 activates the p38 MAPK pathway to contribute to cell death. Lipton and colleagues now report that the p38 MAPK pathway is also the mechanism underlying decreased stem cell proliferation in the brain associated with HIV/AIDS. Under experimental conditions, they were able to neutralize the p38 MAPK pathway and restore stem cell proliferation.
“We show for the first time how HIV/AIDS inhibits proliferation of neural stem cells and prevents the formation of new nerve cells in the adult brain,” said Dr. Stuart Lipton, Director of Burnham’s Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research.
“The fact that the mechanism of action involves the p38 MAPK enzyme is fortuitous because drugs to combat that pathway are being tested for other diseases. If they prove effective, they might also work to protect the brain. Thus, this study offers real hope for combating the bad effects of HIV/AIDS on stem cells in the brain.” Lipton went on to state, “It will be important to see if HIV/AIDS acts similarly on stem cells for other organs in the human body, as this may impact on the disease process as a whole.”
Stuart A. Lipton, M.D., Ph.D. is a practicing neurologist who has worked with HIV/AIDS dementia patients since the identification of the disease in the 1980’s. His pioneering work developing drugs to protect the brain was recognized with Germany’s Ernst Jung Prize in Medicine in 2004.
Along with Lipton, Marcus Kaul, Ph.D., and Shu-ichi Okamoto, M.D., Ph.D., are co-corresponding authors on this paper. Kaul is an Assistant Professor and Okamoto a Research Assistant Professor at Burnham.
This research was supported by grants from the National Institutes of Health.