Todd E. Golde, M.D., Ph.D.
Professor of Neuroscience
Center for Translational Research in Neurodegenerative Disease
Department of Neuroscience
1275 Center Drive
PO Box 100159
Gainesville, FL 32610-0159
Key Words: Alzheimer ’s disease; Amyloid β protein; Neurodegeneration; Neuroinflammation; Therapeutics; Intramembrane proteolysis; Somatic Brian Transgenesis
I am currently the Director of the Center for Translational Research in Neurodegenerative Disease at University of Florida where I direct a robust program of scientific discovery aimed at translating basic discoveries in neurodegenerative disease into diagnostics and treatments for patients. Although I believe the field as a whole has dramatically increased our understanding of the triggers of AD and other neurodegenerative conditions, we have yet to translate these into successful disease modifying therapies. Thus, my laboratory remains committed to opportunistically develop “proof of concept” for novel therapeutic strategies that one day benefit patients with neurodegenerative diseases. Though there is reasonable consensus that misfolded protein accumulation triggers neurodegenerative cascades, the downstream steps in the cascade are much less well understood. Thus, in addition to an “amyloid β protein centric” focus, my laboratory has recently been focusing on factors that may drive the downstream neurodegenerative cascade with a major focus on innate immunity and its role in protecting and driving neurodegeneration. In addition to these scientific foci, in recent years I have been active as an advocate for AD, at both the state and national levels, and have written reviews and perspectives that I believe have helped to focus the field on the issues of prevention and funding levels.
Research Focus & Aims:
The Golde laboratory conducts disease oriented research with a specific, but not exclusive, focus on neurodegenerative disease such as Alzheimer’s disease (AD) and Parkinson’s Disease (PD). Our basic road map for this research is to try and understand the disease, create models that mimic aspects of the disease process in a time course that is amenable to study, identify targets for intervention, and opportunistically develop and evaluate therapies that might alter the disease course. We are a highly collaborative laboratory and believe in leveraging our infrastructure with respect to disease models, knowledge, and technologies to help others move their research forward.
Current Projects in the Golde Lab and the staff who lead these projects are described below.
- Immunotherapeutic approaches for Alzheimer’s disease and other amyloid disease (Yona Levites, PhD, Pedro Cruz PhD).
Aggregation and accumulation of the amyloid β protein in the brain is thought to trigger a complex degenerative cascade that results in Alzheimer’s disease. These studies build on ~10 years of research in the lab and are designed to develop novel active and passive immunotherapies that safely and effectively target Abeta amyloid in AD. Notably these therapies may have benefit in other amyloid diseases.
Funded by the NIH/NIA http://projectreporter.nih.gov/project_info_description.cfm?aid=7796588&icde=5525743 and the MetLife Foundation.
- Gamma-Secretase Modulators and the role of short amyloid pep tides in Alzheimer’s disease. (Thomas Ladd, Brenda Moore PhD).
A longer species of Aβ, Aβ42, is thought to be the key pathogenic molecular in AD. It is critical for deposition of Aβ. Thus, lowering levels of Aβ42 could have a major impact on the development of AD. In collaboration with Dr. Edward Koo’s laboratory (UCSD), we previously demonstrated that select drug and drug-like compounds could modulate Aβ42 production and that this effect was attributable to direct alteration of γ-secretase activity. Drug with this type of effect on Aβ are now referred to as a γ-secretase modulators (GSMs). These studies provided the rationale for clinical testing of GMSs by the commercial sector. Our current collaborative studies are designed to examine more closely how GSMs work, and whether short Aβ peptides are protective.
Funded by the NIH/NIA. http://projectreporter.nih.gov/project_info_description.cfm?aid=8111733&icde=552574
- Therapeutic Targeting of Intramembrane Cleaving Protease. (collaborations with Dr. Wolfe Harvard, Drs. Osborne (U. MASS), Miele (Loyola/U. Miss), M. Bouton (U. FL) and Greenbaum ( U. Penn) DR. Kevin Felsenstein (U. Florida)).
Presenilin is the catalytic component of a multisubunit protease called γ-secretase that cleaves membrane proteins within their transmembrane domains. γ-Secretase cleaves a number of proteins and mediates signal transduction by many of these. In 2003, in collaboration with Dr. Chris Ponting, we identified a family of intramembrane proteases (signal peptide peptidase) that were related to γ-secretase. We are evaluating targeting these proteases in cancer, immunologic disease, and malaria.
Funded by the NIH/NIA. http://projectreporter.nih.gov/project_info_description.cfm?aid=8098929&icde=5525743
- Somatic Brian transgenesis and AAV based models of Neurodegeneration (Yona Levites, PhD, Carolina Ceballos-Diaz, and Paramita Chakrabarty PhD).
We have developed a method using viral vectors to transduce large portions of the neonatal brain. We refer to this technique as somatic Brain transgenesis. Using this technique we can much more rapidly model various aspects of neurodegenerative disease for a fraction of the costs associated with traditional transgenics. We have established over a dozen collaborations based on this technique.
- Inflammatory and Immune Mediators in Neurodegeneration. (Paramita Chakrabarty, Carolina-Ceballos Diaz, Pedro Cruz PhD, Wei Kou PhD).
Recent work from our lab has challenged a long-standing hypothesis that inflammatory processes in AD accelerate Aβ deposition. Unpublished studies also reveal a potential novel role of interferon g in nigrostriatal degeneration. Using the somatic brain transgenic technology described above are broadly explore immune modulators as mediators of neurodegenerative pathways.