|Study Links Alzheimer's Disease to Abnormal Cell Division
A new study in mice suggests that Alzheimer's disease (AD) may be triggered
when adult neurons try to divide. The finding helps researchers understand what
goes wrong in the disease and may lead to new ways of treating it. The study
was funded in part by the National Institute of Neurological Disorders and Stroke
(NINDS), part of the National Institutes of Health, and appears in the January
18, 2006 issue of The Journal of Neuroscience.
For unknown reasons, nerve cells (neurons) affected by AD and many other neurodegenerative
diseases often start to divide before they die. The new study shows that, in
animal models of AD, this abnormal cell division starts long before amyloid plaques
or other other markers of the disease appear. Cell division occurs through a
process called the cell cycle. “If you could stop cell cycling, you might be
able to stop neurons from dying prematurely. This could be a fresh approach to
therapy for Alzheimer's and other diseases, including stroke, amyotrophic lateral
sclerosis [also known as Lou Gehrig's disease], and HIV dementia,” says Karl
Herrup, Ph.D., of Case Western Reserve University in Cleveland, who led the study.
The researchers compared the brains of three different mouse models of AD to
brains from normal mice, looking specifically for markers of cell cycling. They
found that, in the AD mouse models, cell cycle-related proteins appeared in neurons
6 months before the first amyloid plaques or disease-related immune reactions
developed in the brain. Many of the neurons also had increased numbers of chromosomes,
which is typical of cells that have begun to divide. These changes were not seen
in normal mice. The regions of the brain most affected by the neuronal cell cycling
were the cortex and the hippocampus — the same regions most affected in
AD. The cortex is important for thought and reasoning, while the hippocampus
plays a key role in learning and memory. Some parts of the brainstem also showed
evidence of cell cycling.
While the cell cycling appeared to be necessary for neurons to die, it was not
an immediate cause of cell death in the mouse models of AD. Instead, the affected
neurons appeared to live for many months in a near-functional state, with the
mice showing only mild behavioral changes during that time. This suggests that
another type of cellular problem, still unidentified, must damage the neurons
in order for them to die.
The findings shed new light on the theory that the accumulation of amyloid beta
in the brain causes the neuron death in AD. Because the abnormal cell cycling
begins months before the formation of amyloid plaques, it is unlikely that the
plaques themselves trigger the disease process. However, tiny clumps made up
of several amyloid beta molecules (called micro-molecular aggregates) form before
the plaques and may trigger the disease. Since the three mouse models tested
in this study all had mutations in the gene that codes for amyloid precursor
protein, the similarity between affected brain regions in these mice and in people
with AD also supports the amyloid hypothesis.
While previous studies have linked AD to abnormal cell cycling, this is the
first study to examine the link using standard mouse models of AD. The results
indicate that the mice, which do not develop neurofibrillary tangles or the severe
behavioral symptoms of AD, are accurate models of the early cellular processes
that lead to the disease. "The cell cycle markers mimic the human situation rather
well," says Dr. Herrup. "This opens a range of new experimental possibilities
using the cell cycle events as indicators of neuronal distress."
Dr. Herrup and his colleagues are now trying to determine if feeding the mouse
models the drug ibuprofen can stop abnormal cell cycling in neurons and halt
neurodegeneration. Ibuprofen is an anti-inflammatory drug that reduces production
of amyloid beta, and some studies have suggested that it may reduce the risk
of AD. The researchers are also planning additional studies to identify why neurons
start to divide when they are diseased and why entering the cell cycle appears
to trigger cell death.
The work was conducted at Case Western Reserve University's Alzheimer's Disease
Center, which is directed by Dr. Herrup and supported by the National Institute
on Aging, also part of the NIH.
The NINDS is a component of the National Institutes of Health (NIH) within
the Department of Health and Human Services and is the nation’s primary supporter
of biomedical research on the brain and nervous system.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.