Editor's Note: Impaired learning and cognition are commonly seen in individuals with Down syndrome, but the link between the genotype and the phenotype in this syndrome remained ill defined.
Bridging the gap between basic and clinical science, investigators at the Sanford-Burnham Medical Research Institute; the University of California, San Diego (UCSD); and other institutions used mouse models of Down syndrome to study the effects of sorting nexin 27 (SNX27), a protein implicated in memory formation, and isolated a molecular pathway that seems to play a key role in the development of trisomy 21-specific cognitive defects.
In an interview with Medscape, Huaxi Xu, PhD, Professor in Sanford-Burnham's Neurodegenerative Disease Research Program in the Del E. Webb Neuroscience, Aging and Stem Cell Research Center, and William C. Mobley, MD, PhD, Chair of the Department of Neurosciences at UCSD and Executive Director of UCSD's Down Syndrome Center for Research and Treatment, discussed how this collaborative effort will help move the field forward.
A New Approach to Down Syndrome Research
Medscape: Your research focused on identifying the mechanisms behind cognitive dysfunction in Down syndrome. Can you characterize the cognitive symptoms that are typically seen and explain how your research sought to identify its underlying causes?
Dr. Mobley: From their earliest days, individuals with Down syndrome show problems with cognition, learning, and memory, and especially language. With aging, these individuals develop additional difficulties with memory, attention, and an ability to continue abstract cognitive tasks.
In fact, the increasing changes that are seen with cognition in adults have been linked to changes in the brain that mimic those in Alzheimer disease -- amyloid plaques and neurofibrillary tangles -- they begin to occur by age 40 years, and evidence of dementia and loss of cognitive function occurs around age 50 years.
So in individuals with Down syndrome, we begin with a baseline cognition that is compromised and then see a premature onset of dementia associated with the pathology of Alzheimer disease.
Dr. Xu: One common feature these 2 groups share is the beta-amyloid precursor protein (APP), which is encoded by chromosome 21. And we know that amyloid fragments of peptide produced when APP is cleaved are highly toxic to neurons. So it was widely speculated that the additional copy of chromosome 21 effectively led to an "overdose" of beta-amyloid peptide, which contributes to the mechanisms behind the dementia pathology seen in Down syndrome.
Our research looked at this issue from a different angle.
My laboratory has been studying Alzheimer disease for many years, and we had focused on how neurons in Alzheimer disease degenerate or eventually die. One mechanism we looked at was glutamate excitotoxicity, or how excess stimulation of the neurons by glutamate eventually causes slow death or degeneration of the neurons.
One molecule that caught our attention was SNX27, which plays a role in regulating transport of neurotransmitter receptors, such as glutamate receptors. Homozygous knockout Snx27 mice showed a lot of pathologies that are similar to those seen in Down syndrome and Alzheimer disease, but they also died prematurely, only 43 weeks after birth. By contrast, with heterozygous knockout mice, we didn't see as much pathology, but the defects in learning and memory were clearly there. This further clued us in that abnormal levels of SNX27 might be playing a role in cognitive deficits.
Dr. Mobley: The neurobiology of Down syndrome insists that you focus on both early development as well as aging. In the past, Huaxi's lab has focused more on the degenerative changes that are seen in Alzheimer disease -- we are now using the same understandings about degenerative diseases to learn about what goes on during development and to see how early events can serve as a bridge to those that occur later.
This is particularly important in individuals with Down syndrome because although the same extra copy of chromosome 21 is present throughout their lives, the manifestation of cognitive changes is different in development than it is in aging. So looking at what goes on in the developing brain can help us create the context necessary to see changes during aging.
Dr. Xu: And that became very clear when we looked at SNX27 expression. In postmortem human brains from individuals with Down syndrome and a Down syndrome mouse model that we got from Bill's lab, SNX27 expression was significantly reduced, but there is not much of a reduction of SNX27 in Alzheimer patients.
It turns out that SNX27 plays a key role in recycling glutamate receptors and in maintaining a steady-state level of glutamate receptors on the cell surface. But the reduced level of the SNX27 protein in Down syndrome leads to fewer glutamate receptors being recycled back.
Dr. Mobley: Again, this fits nicely with what we have already seen in mouse models of Down syndrome, where there is an imbalance in excitation and inhibition, with inhibition having too prominent a role. So this study helps to understand not just why there is excessive inhibition, but also why excitation is deficient.
Sanford-Burnham Medical Research Institute and Medscape
Cite this: Sorting Out Cognitive Deficits in Down Syndrome - Medscape - Jul 01, 2013.