Following the conclusion of each day during the SFN meeting, our Director of Communications (Rob Goldstein), will publish his thoughts on posters and presentations which he attended. There are thousands of such events each day at the meeting, which was held in San Diego this year. Rob’s view-points and opinions are his own and nothing below is meant to replace the advice a person receives from their personal medical team. You can email marketing@als.net with questions or comments on his recaps. Discussion on these notes and the meeting in general is taking place at the ALS Forum located here: www.als.net/forum
The first poster I found interesting was on Demebolin (our team tested Dimebolin in the SOD1G93A model of neurodegeneration and will be presenting data from that effort later this week). The main focus of the presenter, from the University of St. Louis, was results that suggested that Demebolin, in a preclinical study in AD mice, penetrated into the brain (hippocampus). Her study included 18 mice (10 male and 7 female) which received 1mg/1kg IP for days. The presenter also showed data that suggested that the drug protected against AB metabolism in cell cultures (S.E. Perez, 2010).
Staying on the AD theme, I then proceeded to a poster that showed that interleukin treatment exacerbates tau pathology in 3X transgenic AD mice. Interleukin has also been looked at for potential screens in an ALS mouse, but there were no posters or presentations at this year’s session that reported any new findings (Ghosh, 2010).
A Parkinson’s disease (PD) clinical trial design for a treatment labels snn00031 was reported on in a poster presented by NeuroNova, a biotechnology company located in Belgium. This poster was relevant because the company is also conducting an ALS Phase I trial using their technology. The novel therapeutic system pumps a concentrated form of VEGF from a reservoir located in the abdomen into the cortex. Limited data from the Phase I PD study was reported for the 8 patients enrolled because it is still on-going. However, the presenter did report that so far the treatment seems to be well tolerated by enrollees. The intracerebroventricular system’s batteries need to be replaced every 2-3 years.
Another poster that I visited with Dr. Lincecum of ALS TDI was over on board P3, and dealt with metabolic dysfunction in ALS. The presenter informed us that she executed this project based on past research that had suggested that ALS patients consumed energy at higher rates that normal, even when in a general resting state. Those reports have led to several preclinical and clinical investigations, including high-fat/calorie diets in mice and patients. In this poster, the researcher focused on a hypothesis that decreased AMPK function would be beneficial. The complex presentation included data from in vitro (cell-based) experiments that showed that a reduction in AMPK activity is beneficial to the survival of cells. In explaining in vivo experiments, which was conducted by a G85R worm model, she reported that there was an improvement in locomotion when she reduced AMPK activity. The researcher reported that she hopes to complete an experiment in a mouse model of ALS and report those findings in the future (Lim, 2010). On the ALS Forum, there has been much interest by some members in metabolic dysfunction in ALS. You can read a thread on that subject, which includes links to other findings in this area by clicking here.
An interesting observation reported at this years Society for Neuroscience Annual meeting was that there seems to be a reduction in Renshaw interneurons in SOD1G93A mice before clinical signs of ALS were presented The researchers pulled tissue at various time points from a group of 30 animals and found markers of apoptosis in only a single case. There was no clear hypothesis for why these specific interneurons where missing (Carr, 2010).
There were several TDP-43 related posters presented. There were a plethora of definitions of what “TDP-43” and how it relates to neurodegenerative disease. For my purposes, and for yours, I will simply define TDP-43 as a protein of interest to researchers in several neurodegenerative disease fields, including ALS and FTD. Researchers are interested in this protein after several recent publications have correlated its presence outside the nucleus of motor neurons to the clinical diagnosis of neurodegenerative disease. The role of the protein in disease onset (or progression) is wholly unknown at this time.
Work from a researcher at UCSF showed that TDP-43 is neurotoxic when it is present in the cytoplasm (Barmada, 2010). That finding alone isn’t necessarily novel, but the work deserves special note because it was the only poster (thus far) that dealt with trying to set the stage for why researchers should look at TDP-43 at all. Most other presentations assumed consensus on TDP-43’s relevance to disease and moved on to creating models of disease. On Saturday, I saw a University of Montreal researcher report on a zebrafish model of TDP-43 (Lissouba, 2010) (also there was a zebrafish FUS model presented as well). on Sunday there was a fruit-fly model of TDP-43 that showed the desired neurotoxic effect (Ihara, 2010) as well as a poster by the Washington University of St. Louis group that described their murine model of TDP-43 aggregation (Wegorzewska, 2010).
Although I didn’t attend the NINDS “Advances in Disease Modeling for ALS and FTD Workshop” on Friday, several of our staff did. Dr. Perrin was an invited guests speaker for the afternoon panel that concluded the event. With nearly 200 of the country’s most well-known and accomplished neuroscientists in the room, the discussion at some point likely jumped from high-level or nitty-gritty. However, I spoke with several people that attended the Friday meeting, including Drs. Perrin, Lincecum, and Rothstein and they all agreed that it was an important step in the right direction in building consensus in the field about how model’s for TDP-43 and FUS could best be used. Dr. Perrin said that his biggest concern is that researchers may jump too quickly into using the current available models of TDP-43 for efficacy screening. Dr. Perrin pointed out that based on the current work available on one of the models proposed; it would take several hundred animals to identify a statistically relevant signal. He illustrated that a tightening of the models is possible and urged his colleagues to focus on creating reliable and predictable tools.
Works Cited
Barmada, S., at al. (2010). A TARBDP mutation associated with familial amytrophic lateral sclerosis induces neuronal toxicity through cytoplasmic mislocalization of TDP-43. Gladstone Institute of Neurological Disorders, Departmentof Neurology, USCF Medical Center. San Francisco: Soceity for Neuroscience 40th Annual Meeting.
Carr, P., et al. (2010). Interneuron loss in a mouse model of amytrophic lateral sclerosis. University of North Dakota, Depatment of Anatomy and Cell Biology. Grand Forks, ND, USA: Society of Neuroscience 40th Annual Meeting.
Ghosh, S., et al. (2010).Sustainedoverexpression of Interleukin-1B ameliorates plaque pathology but exacerbates tangle pathology in the triple transgenic mouse model of Alzheimer's disease. University of Rochester, School of Medicine and Dentistry. Rochester, NY: Society for Neuroscience 40th Annual Meeting.
Ihara, R., et al. (2010). RNA binding mediates neurotoxicity in the Drosophila transgenic model of TDP-43 proteinopathy. Graduate School of Medicine, University of Tokyo, Department of Neurology and Depatment of Neuropathology. Bunkyo-ku, Tokyo, Japan: Society for Neuroscience 40th Annual Meeting.
Lim, M., et al. (2010). Reduced activity of AMP-activated protein kinase (AMPK) is protective in models of amytrophic lateral sclerosis (ALS). University of Pennsylvania, Department of Neuroscience. Philadelphia, PA, USA: Society for Neuroscience 40th Annual Meeting.
Lissouba, A., et al. (2010). Developing a model of TARDBP mutations in amytrophic lateral sclerosis using zebrafish. University de Montreal, Quebec, Patholgie et Biologie Cellulaire. Montreal, Canada: Society for Neuroscience 40th Annual Meeting.
S.E. Perez, et al. (2010). Demebon interaction with amyloid metabolism in the hippocampus of 3x-Tg-AD mice. Rush University Medical Center, Department of Neurological Science. Chicago, IL: Society for Neuroscience 40th Annual Meeting.
Wegorzewska, I., at al. (2010). Development and charectorization of inducible wild-type and mutant TDP-43 transgenic mice. Washington University of Saint Louis. St. Louis, MO, USA: Society for Neuroscience 40th Annual Meeting.
The Friday NINDS “Advances in Disease Modeling for ALS and FTD Workshop” information and agenda can be found here.
To read abstracts cited, please visit www.sfn.org/am2010 and click on “Neuroscience Meeting Planner” then search by author last name. That should be the quickest route.