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Gene Gives Insight into Down Syndrome and Alzheimer's
Disease
Many of the symptoms of both Alzheimer's disease (AD) and Down syndrome (DS)
are caused by degeneration of cells in the brain called basal forebrain cholinergic
neurons (BFCNs). A new study in mice shows that a gene tied to AD may be involved
in the degeneration of these cells in both diseases. The finding points the way
for new strategies to try to treat these conditions.
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| A healthy neuron. Image courtesy of the Alzheimer's
Disease Education and Referral Center, a service of NIH’s National
Institute on Aging. |
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DS is the most frequent genetic cause of mild to moderate mental retardation. It's
usually caused by an error that results in a sperm or egg with an extra copy of
chromosome 21. On that chromosome is the amyloid precursor protein gene (App),
which is involved in AD. People with DS develop changes in brain structure like
those seen in AD, including the loss of selected groups of neurons like BFCNs.
A team of researchers led by Dr. William C. Mobley and Dr. Ahmad Salehi of Stanford
University set out to investigate whether it was the higher effective "dose" of
App that might lead to the symptoms of DS.
With support from three different NIH institutes and other funding sources,
the researchers genetically engineered mice with additional third copies of about
140 mouse genes that are equivalent to the genes in a region of human chromosome
21 that's associated with DS. They created two other mouse strains without App
for comparison: one with a partial set of about 100 of the 140 genes, and another
with all of them except for App.
In the July 6, 2006, issue of Neuron, the team reports that a higher
dose of App decreased the transport of a key molecule called nerve growth factor
(NGF) that's important for the maintenance and survival of nerve cells in the
brain. NGF is normally taken up by the cells and transported within, where it
alters the expression of many genes.
The mice with the full set of extra genes had only 4% of the NGF transport levels
of control mice. The mice with all of the extra genes except for App had NGF
transport levels 56.2% that of the control mice, showing that the extra App gene
significantly interferes with normal NGF transport. The mice with only the partial
set of extra genes had levels higher than either, 70%, showing that extra App
wasn't the only factor inhibiting NGF transport in the other mice. When the researchers
looked at the BFCNs under the microscope, they saw significant degeneration in
the mice with the extra App genes.
This study suggests that too much App, by inhibiting NGF transport and thus
bringing about the degeneration of BFCNs, may be at least partially responsible
for some symptoms in both DS and AD. The researchers found signs of how App might
affect transport, opening opportunities for further investigation. In the future,
strategies to counter higher doses of App may prove a successful way to treat
these diseases.
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