Research Initiatives from DSRTF...
Current Potential Therapeutic Targets
APP in Down Syndrome
To extend their discovery that the over-expression of the specific APP gene, also known to be encoded on human chromosome 21 and associated with the pathology of Alzheimer's disease, is involved in cognitive impairment in a mouse model for Down syndrome (1), recent DSRTF-funded research by Dr. Mobley and his collaborators is progressing to identify additional specific details involved in this impaired molecular mechanism as well as potential drug compounds that will reduce the level of APP expression. Together with Dr. Steven Chu, a Nobel Laureate in physics, Dr. Mobley and their colleagues very recently developed a novel quantum-dot based technique (2) that may provide an approach to further define the APP-mediated impairment as well as a novel method to identify additional potential drug compounds affecting the process. It should be noted that this very interesting mechanistic linkage between Down syndrome and Alzheimer's disease suggests that not only may individuals with Down syndrome potentially benefit from the on-going specific research and development for new Alzheimer's disease drugs, but that individuals with Alzheimer's disease might also potentially benefit from DSRTF-supported Down syndrome research.
GABA-A mediated Inhibition in the Dentate Gyrus
Building on earlier DSRTF-funded research by Dr. Mobley and his collaborators (3), Dr. Garner and his colleagues published exciting research results in April (4) demonstrating that potential drug compounds which inhibit GABA-A receptors, such as pentylenetetrazole (PTZ), dramatically improve cognitive function in a mouse model of Down syndrome. This DSRTF-supported research has advanced the field another promising step toward realizing an effective treatment to improve cognition in individuals with Down syndrome. Dr. Garner and his collaborators are continuing their research to test and evaluate the potential of these compounds for a new treatment strategy and gain further insight to how they produce effects on cognition. Further, since the trisomic gene(s) involved in the specific cognitive processes studied in this research remain unknown, they have also recently published studies (5) suggesting differences in the hippocampal pathology between two different mouse models of Down syndrome that may help narrow the search for such gene(s).
Exploring New Research Directions
Additional recently published DSRTF-funded research addresses the further definition of specific biological mechanisms underlying the cognitive impairment in Down syndrome. Dr. Dan Madison and his collaborators have discovered specific neuronal circuit abnormalities in a distinct area of the hippocampus, the CA3 region, in the Ts65Dn mouse model of Down syndrome which appear to result in "reduced-complexity networks" and may affect memory functions in Down syndrome (6). Interestingly, subsequent research in Dr. Madison's laboratory revealed parallel results relating to cognitive dysfunction in a mouse model for Fragile X syndrome (7). Dr. Mobley and his colleagues also recently reported research studies analyzing genotype-phenotype relationships involving specific synaptic structural and functional alterations linked to cognitive dysfunction in two different mouse models of Down syndrome (8). Importantly, they also continue an intense pursuit to develop a more comprehensive model interrelating each of the identified dysfunctional mechanisms with cognitive impairment in Down syndrome. These studies are providing critical new experimental information that promises to be helpful in identifying additional potential therapeutic targets.
Inaugural DSRTF Scientific Advisory Board (SAB) Meeting
DSRTF established the SAB as an integral element of the Foundation's proactive research strategy, especially in identifying the most promising ideas and research, advising on research resource allocations, and providing expertise and critical perspective on DSRTF-supported research. The SAB members represent a highly distinguished group of scientists and physicians, with expertise encompassing the fields of Down syndrome research, neuroscience, including Alzheimer's disease research, molecular cell physiology and metabolism, genetics/genomics, and drug discovery. During the inaugural SAB meeting in February there was a lively interactive review of the current DSRTF-supported research considered by all to be constructive and productive, and the SAB concluded there had been exceptional research progress as described above. Based on further vigorous discussions among the SAB members, it is clear there are many additional promising research areas, e.g. postnatal neurogenesis, sleep and metabolic dysfunctions and other specific opportunities, with highly significant potential for an even deeper understanding of cognitive impairment in Down syndrome. Accelerating the discovery and development of new therapies can be effectively achieved through parallel pursuit and support of such an increased diversity of research, and key to realizing this goal will be an expansion of research funding to reach a meaningful critical mass, an increasingly important role for DSRTF. As DSRTF develops and implements new research initiatives based on close consultation with the SAB, we look forward to presenting and sharing the Foundation’s continuing progress in future updates.
Numbered Citations; for web links and additional information, see:
1. Neuron 51, 29 (2006);https://owa016.msoutlookonline.net/owa/redir.aspx?URL=http%3a%2f%2fwww.neuron.org%2fcontent%2farticle%2fabstract%3fuid%3dPIIS0896627306004144; and, http://www.dsrtf.org/dsnews-071806.html
2. Proc Natl Acad Sci U S A 104,13666 (2007); www.pnas.org/cgi/content/abstract/104/34/13666
3. J Neurosci. 24, 8153 (2004); www.jneurosci.org/cgi/content/full/24/37/8153
4. Nat Neurosci.10, 411 (2007); https://owa016.msoutlookonline.net/owa/redir.aspx?URL=http%3a%2f%2fwww.nature.com%2fneuro%2fjournal%2fv10%2fn4%2fabs%2fnn1860.html; and, http://www.dsrtf.org/news-022507.htm
5. Neuroscience Letters 421, 137 ( 2007)
6. J Physiol. 579, 53 (2007); http://jp.physoc.org/cgi/content/abstract/579/1/53
8. J Comp Neurol. 504, 329 (2007); www3.interscience.wiley.com/cgi-bin/abstract/114298666/ABSTRACT