Basic Research

Our Goal

Treatments that enhance the lives of people with Down syndrome

The ultimate goal of our research is to cultivate treatments that enhance the lives of people with Down syndrome, making it possible for them to achieve more independence as both children and adults.

We know that people with Down syndrome have difficulties with brain function, including problems with learning, memory and speech throughout life, as well as the onset in later life of increased cognitive problems associated with the brain changes of Alzheimer's disease.

Our Approach

Using advances in gene sequencing and neurosciences to define the cause

Effective treatments will only emerge from a careful, comprehensive and scientific approach to understanding the cause of cognitive problems in people with Down syndrome.

Starting with the genetics of Down syndrome, we know that all of the changes are due to an extra copy of chromosome 21 (Trisomy 21), with all of its genes and regulatory sequences. Thus, defining the cause for problems begins by discovering the genes and cellular mechanisms responsible.

Recent advances in gene sequencing, including the completion of the Human Genome Project, as well as advances in neuroscience, bring us closer than ever to achieving our goal. Indeed, we are optimistic that effective treatments for the problems faced by people with Down syndrome and their families are on the horizon. It is difficult to make exact predictions, but with continued progress we think that important advances will be made within the next decade and possibly sooner.

Examining brain circuit function involved in cognition

We are working to define the genes and mechanisms responsible for cognitive problems in Down syndrome. The challenge is to find the genes responsible and to pinpoint how an extra copy of these genes causes problems.

We begin with the hypothesis that changes in cognition must be due to dysfunction of the brain circuits responsible for cognitive function. This hypothesis is supported by a basic principle of neuroscience that the operation of circuits determine all brain function. Accordingly, all changes in brain function must be due to changes in circuit function.

Circuits are composed of neurons connected to one another, so the changes in brain circuits will be found in the structure and function of neurons or in the connections that neurons make with one another.

The point at which one neuron communicates with another is called the synapse. A synapse allows for a neuron to excite the next neuron in the circuit, thus forming an excitatory synapse; alternatively, a synapse may allow one neuron to inhibit the activity of another neuron, thus forming an inhibitory synapse.

• Normal circuit function requires the proper balance of excitation and inhibition.
• Too much excitation could cause a seizure.
• Too much inhibition could block cognitive function.

Synaptic changes are often at the core of disorders of brain function and studies from our lab and many others demonstrate that this also applies to Down syndrome. Our quest is supported by mice that genetically model Down syndrome. They are engineered to contain some or all of the mouse genes whose human counterparts are found on human chromosome 21.

The research begins with carefully and quantitatively cataloging brain changes most likely to cause cognitive issues. We examine the brain circuits involved in cognition, including circuits known to be changed in people with Down syndrome.

Restoring balance of neural circuits to improve learning and memory

As indicated above, brain circuit function requires the formation and function of synapses and the creation of a proper balance of excitation and inhibition. Studies of mice have shown that synapses in brain circuits known to be affected in Down syndrome are abnormal in both structure and function. Both the synapses and the spines that contain them are enlarged, suggesting an underlying problem with their function.

The most important finding to date is that excessive inhibition leads to an imbalance that compromises circuit function. When the brain circuits do not fire as actively as they should, learning and memory are impaired.

We are actively on the hunt for the genes responsible for this imbalance along with how to restore cognition to normal levels in animal models. Recent progress is very encouraging with respect to both narrowing down the genes and the means by which they work. In recent studies we have been able to enhance cognition in the mouse model by interrupting inhibition through a specific class of inhibitory receptors.

This exciting research could benefit people with Down syndrome ultimately by helping them learn and remember better.

Keeping circuits well during aging

Patients with Down syndrome represent the single largest group of people in the world with genetically based Alzheimer's disease. They are predisposed to develop the disease, and most appear to do so by middle age.

What gene(s) is responsible and how does it cause the problem? Clues from the literature about the genetic causation in Alzheimer disease in the non-Down syndrome population point to the Amyloid Precursor Protein (APP) gene. This gene lives on chromosome 21. Because there is an extra copy of APP in people with Down syndrome, it is logical to ask if it plays a role in causing dementia in Down syndrome.

In mouse models of Down syndrome we indeed showed that the extra copy of the APP gene does play a prominent role in the death of neurons in older people with Down syndrome and those with typical Alzheimer's disease. When we eliminated the extra copy of APP, neurons that otherwise would have died now survived. It is now clear that an extra copy of the APP gene and an increase in the protein it encodes, called the APP protein, are culprits.

How does too much APP hinder brain circuits in people with Down syndrome? We recently discovered evidence pointing to changes in the movement of the protein within the neuron and alteration in the way it is cut by certain enzymes. One of the products is a peptide called Abeta. This piece of APP appears to be toxic to neurons and its increasing presence in the brain characterizes people with Alzheimer's disease, including those with Down syndrome. As these studies progress, we hope to find new treatments that protect people with Down syndrome from developing Alzheimer's disease.

Our studies point to another feature of neuron loss in the mouse model of Down syndrome that may lead to a new treatment for enhancing cognition in people, using a medicine that is already available. One aspect of the brain changes was the death of neurons in the brainstem that are connected to neurons in the cortex and hippocampus. These neurons make the neurotransmitter norepinephrine and are also lost in older people with Down syndrome and in those with Alzheimer's disease.

Because the neurons are dying, norepinephrine levels in the brain are low and the circuits that include these neurons become dysfunctional. We found that boosting norepinephrine reversed cognitive decline. This gives us the hope that the same treatment might help people with Down syndrome.

From Research to Treatment

Next step: Applying discoveries to the care of people with Down syndrome

The past several years have seen unprecedented progress in understanding the genes and mechanisms that compromise cognition in people with Down syndrome. To achieve our goal of helping people with Down syndrome, we must translate these basic research discoveries to the clinic.

We are now entering the era in which rational, careful trials of new treatments are possible. We are working with three companies to determine how to conduct rigorous clinical research studies and clinical trials.

Participation by people with Down syndrome will determine the success of these trials. In addition, a new technology allows us to view the deposition of the Abeta peptide in the brains of people with Down syndrome. This will make it easier to monitor for the onset of Alzheimer's and to evaluate potential drugs for treating it. We look forward to partnering with academic and industrial colleagues as well as the Down syndrome community to achieve our goal of improving the lives of children and adults with Down syndrome.

More about our clinical research