AIDS Interferes With Stem Cells In The Brain
August 15, 2007
Science Daily — 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.
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."
These findings were made available to medical researchers through
priority publication online by the journal Cell Stem Cell.
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.
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.
.
Note: This story has been adapted from a news release issued by
Burnham Institute.
http://www.scienced
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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