Neuron Finding Lifts Hopes for Down Syndrome Drug
An abstract of “Neurobiological Elements of Cognitive Dysfunction in Down Syndrome: Exploring the Role of APP”
Down syndrome is usually due to each cell
in the human body having three copies, rather than two copies, of
chromosome 21. This heartbreaking illness leads not just to a spate of
physical abnormalities and cognitive dysfunction, but often to
early-onset Alzheimer’s disease.
A pivotal brain region affected by Down
syndrome is the hippocampus. Now scientists at Stanford University
School of Medicine have made two important findings about what occurs in
that region in a mouse model of Down syndrome, which purportedly
translates to people with the syndrome.
One is a loss of two types of
neurotransmitter-producing neurons in the
hippocampus—acetylcholine-producing neurons and norepinephrine-producing
neurons. The other is that this loss is linked with the overexpression
of the amyloid precursor protein gene in the hippo-campus. Mutations in
this gene, which is located on chromosome 21, are known to lead to
early-onset Alzheimer’s, and it may be that early onset of Alzheimer’s
pathology in people with Down syndrome is due in part to overexpression
of the amyloid precursor protein gene.
These findings have provocative
therapeutic implications for people with Down syndrome, the scientists
also pointed out online September 27 in Biological Psychiatry.
For instance, although the amyloid precursor protein gene should be a
primary therapeutic target in Down syndrome, there are no safe and
effective medications on the market to reduce the gene’s expression. In
contrast, since a paucity of norepinephrine-producing neurons in the
hippo-campus also seems to contribute to Down syndrome, medications that
enhance norepinephrine levels in the brain and are already on the
market to treat attention-deficit/hyperactivity disorder might be of
therapeutic benefit to individuals with Down syndrome. Moreover, such
medications might also subdue the action of the amyloid precursor
protein gene in such individuals, they speculated.
“We are indeed working on this group of
drugs—drugs that are able to increase norepinephrine levels and that
have already been approved by the Food and Drug Administration—in our
mouse models,” Ahmad Salehi, M.D., Ph.D., a clinical associate professor
of psychiatry at Stanford and the study’s senior investigator, told Psychiatric News. “This strategy could speed up the development of a treatment for cognitive function in Down syndrome enormously.”
The scientists’ discovery of a paucity of
acetylcholine-producing neurons in the hippocampus of an animal model of
Down syndrome holds therapeutic promise, the researchers noted. In
fact, other researchers reported eight years ago that the Alzheimer’s
drug donepezil, which slows the break down of acetylcholine in the
brain, might improve cognitive scores and expressive language in
children and adults with Down syndrome.
Yet if donepezil improves cognitive
function and language in these individuals, is there reason to believe
that medications that increase norepinephrine would be superior to
donepezil in that regard? Asalehi believes there is. “I think using
norepinephrine-ergic drugs would be far superior to cholinergic ones for
the following reasons: The norepinephrine system has some regulatory
effects on the cholinergic one. It has been shown that lesions in the
former lead to increased severity of cholinergic deficits; most adults
with Down syndrome will show Alzheimer’s-related pathology, particularly
amyloid plaques. There are new studies showing that increasing
norepinephrine levels in mouse models of Alzheimer’s significantly
reduce amyloid accumulation. These findings suggest that using
norepinephrine-ergic drugs might not only restore cognition in kids with
Down syndrome, but also reduce Alzheimer’s-related pathology in adults
with the syndrome.”
“Studies such as this one help to further
our overall understanding of central nervous system function and in
particular differences seen in individuals with Down syndrome,” Melanie
Manning, M.D., director of the Center for Down Syndrome at Stanford’s
Lucile Packard Children’s Hospital, told Psychiatric News. “Many
of the families of individuals with Down syndrome follow results from
research studies such as this one with great interest. They express a
desire to learn more about potential clinical applications that lie
ahead.”
The research was funded by the Mental
Illness Research, Education, and Clinical Center Department of Veterans
Affairs; Down Syndrome Research and Treatment Foundation; Thrasher
Foundation; and Alzheimer’s Association.
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