biology

The Link between

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medicine

Down Syndrome and

Alzheimer’s Disease by
Lauren Mamer

W
hat does Down Syndrome have in common with corresponds to trisomy 21 in humans--to model the effects of
Alzheimer’s disease? Down Syndrome is a common Down Syndrome. Four major abnormalities in the neurons of the
genetic disorder that causes delayed physical and hippocampus were observed in these mice: enlarged synapses,
cognitive development from birth. It affects over increased inhibitory signaling, a failure to transport nerve
350,000 people in the United States alone, and 1 out of every growth factor (NGF) from the hippocampus to the cell bodies
1,000 live births. Alzheimer’s is a neurological disorder that is of cholinergic neurons- neurons that transmit acetylcholine and
associated with aging in otherwise normal individuals. However, are critical to memory and learning, and atrophied cholinergic
individuals with Down Syndrome develop Alzheimer’s by age 40, neurons. The failure to transport NGF and the atrophied neurons
suggesting that the genes that contribute to Down Syndrome may are also seen in Alzheimer’s patients, suggesting a possible
be implicated in Alzheimer’s as well. genetic link between Down Syndrome and Alzheimer’s.

Down Syndrome and the Mouse Model The Transport of Nerve Growth Factor (NGF)
Down Syndrome occurs when an individual is born with three NGF is a protein produced in the hippocampus that regulates
copies of all or part of chromosome 21, a condition called trisomy the development and ongoing survival of cholinergic neurons.
21. The human genome is normally diploid, meaning that there In order for NGF to function in maintaining cholinergic neurons,
are two copies of each chromosome. Having an extra copy of it must be transported from the hippocampus, through the axon
chromosome 21 means that the of the cholinergic
genes in that chromosome will
be overexpressed.
NGF is a protein produced in the neuron, and into
the cell body of
The
neurological
most significant
effects of
hippocampus that regulates the the neuron.
this
If
transport
Down Syndrome are in the
hippocampus, a region of the
development and ongoing survival of is inhibited for
any reason, the
brain that plays a central role
in long-term memory and
cholinergic neurons. cholinergic neurons
shrink in size and
learning. To further explore cease to function
properly. Dr.
the physiology Mobley’s lab looked at NGF transport and found that NGF
of the disease, inhibition resulted in the atrophy of cholinergic neurons in the
Dr. William Down Syndrome mouse model.
C. Mobley, Dr. Mobley’s team discovered that the neuronal atrophy is
Professor and due to a transport failure rather than to a lack of NGF altogether.
Chair of the When NGF is injected into the hippocampus, the neurons
Department of remain defective. However, when axonal transport is bypassed
Photo Credit: Dr. William C. Mobley

Neurology and by injecting NGF directly into the cell bodies of the cholinergic
Neurological neurons, they become fully functional.
Sciences at This transport failure was visualized by Mobley using
the Stanford a mechanism of viewing axonal transport developed in
School of collaboration with Steve Chu of the University of California,
Medicine, and Berkeley. With this method, axons are separated from the cell
his colleagues, bodies and individual NGF molecules are visualized as they are
Mouse models of Down Syndrome, such as the one seen
used a mouse transported along the axon. Mobley and his colleagues were able
here, are used to more closely study the physiology of with trisomy to visualize the decreased transport of NGF in Down Syndrome
the disease. 16--which mice compared to normal mice.
Exposure of the neurons to NGF not only reverses the
20 stanford scientific
 atrophy biology
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Exposure of the neurons to NGF not only reverses medicine
the atrophy of existing cholinergic neurons, it actually
causes them to increase in number. This suggests that
the symptoms of Alzheimer’s and the corresponding
symptoms of Down Syndrome are not a result of
cholinergic neuron death, but instead are a result of
atrophied, non-functional cholinergic neurons. Thus,
the degeneration of neurons could be reversible with
treatment.

Photo Credit: Dr. William C. Mobley

Finding the Guilty Gene
To narrow down the genes responsible for specific
defects seen in the Down Syndrome mice, Dr. Mobley
and his colleagues Craig Garner, Robert Malenka, Daniel
Madison, and Charles Epstein studied another type
of mouse whose genome had three copies of a smaller
portion of chromosome 16 than Mobley’s original Down
Syndrome model mice. In addition to displaying fewer Some of the neuron degeneration that occurs in Alzheimer’s disease can be seen on a large
symptoms than the original mice, NGF transport across scale as shown in this picture that compares a normal brain to one from an individual with
Alzhiemer’s Disease.
the axons of the cholinergic neurons was normal in the
second set of mice and the neurons were healthy. This in regulation of NGF transport. To investigate further, normal
observation meant that at least one of the genes that was restored male mice carrying only one copy of the APP gene were crossed
to its normal with original Down Syndrome females. The resulting offspring
the degeneration of two copy state displayed a variety of genotypes, including normal, diploid
in the second mice with one or two copies of the APP gene, as well as Down
the neurons due to set of mice was Syndrome mice with either two or three copies of the gene. It
responsible for turned out that the Down Syndrome mice with only two copies
age could be reversible inhibiting the of the APP gene had significantly more NGF transport than
transport of NGF the Down Syndrome mice with three copies of the gene. The
with treatment in the Down deletion of just one copy of the APP gene in a Down Syndrome
Syndrome mice. mouse restored the transport of NGF from less than 10% of the
This criterion transport occurring in a normal cell to almost 60%. Doing so
allowed Mobley also prevented the atrophy of the cholinergic neurons and thus
and his colleagues to narrow the potential culprits to a group of the pathology of Alzheimer’s, suggesting that APP is at least one
40 genes that was present in three copies in the original Down gene responsible for NGF transport failure and the pathogenesis
Syndrome mice, but only present in two copies in the second of Alzheimer’s.
group of mice.
Out of these 40 candidate genes, one of them caught the Research Implications
lab’s attention. The APP gene – coding for amyloid precursor Mobley’s research, revealing the importance of the APP gene
protein - was thought from previous studies to play a critical role in the mouse model, complements recent evidence that the over-
expression of amyloid precursor protein in humans is the cause
of certain cases of inherited Alzheimer’s. This raises exciting
speculation that the over-expression of APP might be the general
cause of Alzheimer’s. Furthermore, the fact that deleting a copy
of the gene in Down Syndrome mice significantly improved the
transport of NGF suggests that it might be possible to prevent or
reverse the disruption of NGF transport—and thus Alzheimer’s—
by decreasing the expression of the APP gene to normal levels.
Mobley’s team is working to further investigate this topic. They
are convinced that by focusing efforts on thorough science and
understanding the cell biology, genetics, and neuroanatomy
behind Down Syndrome and Alzheimer’s, it will be possible to
develop effective treatments for these conditions. S

Courtesy of Dr. William C. Mobley

Lauren Mamer is a freshman majoring in biological sciences. In addition

A diagram of where NGF transport occurs between the hippocampus and the
cell bodies of the basal forebrain cholinergic neurons. This transport is blocked to writing for the Stanford Scientific, she enjoys surfing and running and
in Alzheimer’s and in the Down Syndrome mice. eventually wants to go to medical school.

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