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Dr. Todd Golde

Therapeutic Approaches to Neurodegenerative Disease

Dr. Todd GoldeDirector, CTRND;
Director, 1Florida ADRC;
Professor, Neuroscience;
Investigator, McKnight Brain Institute and CTRND

Residency, Clinical Pathology and Laboratory Medicine, University of Pennsylvania, 1994-1996
Post Doc, Institute of Pathology, Case Western Reserve University, 1990-1992
MD, Medicine, Case Western Reserve University, 1994
Ph.D., Pathology, Case Western Reserve University, 1991
B.A., Biology/Immunology, Amherst College, 1985



Contact Dr. Golde
Phone: 352-273-9458

Research Focus
Dr. Golde’s laboratory conduct’s disease oriented research with a specific, but not exclusive, focus on neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson 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 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

  1. 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 laboratory and are designed to develop novel active and passive immunotherapies that safely and effectively target Aβ amyloid in AD. Notably these therapies may have benefit in other amyloid diseases. Funded by the NIH/NIA and the MetLife Foundation.
  2. Gamma-Secretase Modulators and the role of short amyloid peptides 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 oon 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.
  3. Therapeutic Targeting of Intramembrane Cleaving Protease. (Collaborations with Michael Wolfe (Harvard), Barabara Osborne (U. MASS), Lucio Miele (Loyola/U. Miss), Michael Boulton (U. FL) and Doron Greenbaum ( U. Penn)).. 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.
  4. Proteinopathy induced Senescence Reponses in Neurodegenerative Disease (Wei Kou PhD, Paramita Chakrabarty PhD). We are exploring an alternative way in which protein accumulation in the brain might lead to brian organ failure. We hypothesize that protein misfolding and aggregation triggers a self-reinforcing cycle of chronic stress (sub-lethal toxicity), pro-inflammatory signals and a senescence response (Golde and Miller, Alz Res Ther 2009). We will examine whether under stress, neurons can undergo changes that phenocopy aspects of replicative senescence and whether these senescent changes are accelerated in Alzheimer’s disease  and other neruodegenerative diseases.  Funded by the Ellison Senior Scholar Award.
  5. 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. We welcome collaborations and are also willing to provide training in this methodology.
  6. Inflammatory and Immune Mediators in Neurodegeneration. (Paramita Chakrabarty PhD, Carolina Ceballos-Diaz, Pedro Cruz PhD, Wei Kou PhD). Recent work from our lab has challenged a long-standing hypothesis that inflammatory processes in Alzheimer’s diseaseaccelerate Aβ deposition. Unpublished studies also reveal a potential novel role of interferon γ in nigrostriatal degeneration. Using the somatic brain transgenic technology described above we plan to more broadly explore immune modulators as mediators of neurodegenerative pathways.
  7. Effects of IL-10 on Neurodegeneration in Mutant Alpha-Synuclein Transgenic Models.(Paramita Chakrabarty PhD, Yona Levites PhD, Jacob Ayers PhD, Carolina Ceballos-Diaz We are testing the hypothesis that IL-10 will be protective in a model of neurodegeneration induced by alpha-synuclein that is highly relevant to human PD. We predict that IL-10 will be protective. However, the precise role of inflammation in PD and other neurodegenerative disorders remains enigmatic. Thus, other outcomes including accelerating disease in this model are possible, but nevertheless will be informative.

Join the team!

Postdoctoral Associate- Requisition number- T2116

The basic road map for research in the Golde laboratory is to try to 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 research foci include 1) developing both targeted immunotherapies for neurodegenerative disease, ii)  harnessing innate immunity in an attempt to  provide disease modification in neurodegenerative disease, iii) refinement of rAAV based gene delivery to the brain and spinal cord, iv) using systems biology in collaboration with the Institute for Systems Biology to guide therapeutic target development, and v) providing an enhanced understanding of the pharmacokinetics and distribution of biologics in the brain and spinal cord.  Postdoctoral candidates in the Golde laboratory have a track of productivity with high impact publications with successful advancement to both academic faculty positons and positions in industry.

Please apply for this position through University of Florida website.

Selected Publications

  • Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG. (1992) Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science, 255, 728-30.
  • Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai XD, McKay DM, Tintner R, Frangione B, et al. (1992) Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science 258:126-129.
  • Cai XD, Golde TE, Younkin SG. (1993) Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science, 259, 514-6.
  • Das P, Murphy MP, Younkin LH, Younkin SG, Golde TE. (2001) Reduced effectiveness of Abeta1-42 immunization in APP transgenic mice with significant amyloid deposition. Neurobiol Aging, 22, 721-7.
  • Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, Findlay KA, Smith TE, Murphy MP, Bulter T, Kang DE, Marquez-Sterling N, Golde TE, Koo EH. (2001) A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature, 414, 212-6.
  • Ponting CP, Hutton M, Nyborg A, Baker M, Jansen K, Golde TE. (2002) Identification of a novel family of presenilin homologues. Hum Mol Genet, 11, 1037-44.
  • Das P, Howard V, Loosbrock N, Dickson D, Murphy MP, Golde TE. (2003) Amyloid-beta immunization effectively reduces amyloid deposition in FcRgamma-/- knock-out mice. J Neurosci, 23, 8532-8.
  • Eriksen JL, Sagi SA, Smith TE, Weggen S, Das P, McLendon DC, Ozols VV, Jessing KW, Zavitz KH, Koo EH, Golde TE. (2003) NSAIDs and enantiomers of flurbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest, 112, 440-9.
  • Kukar T, Murphy MP, Eriksen JL, Sagi SA, Weggen S, Smith TE, Ladd T, Khan MA, Kache R, Beard J, Dodson M, Merit S, Ozols VV, Anastasiadis PZ, Das P, Fauq A, Koo EH, Golde TE (2005) Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production. Nat Med 11:545-550
  • McGowan E, Pickford F, Kim J, Onstead L, Eriksen J, Yu C, Skipper L, Murphy MP, Beard J, Das P, Jansen K, Delucia M, Lin WL, Dolios G, Wang R, Eckman CB, Dickson DW, Hutton M, Hardy J, Golde T. (2005) Abeta42 is essential for parenchymal and vascular amyloid deposition in mice. Neuron, 47, 191-9.
  • Levites Y, Jansen K, Smithson LA, Dakin R, Holloway VM, Das P, Golde TE. (2006) Intracranial adeno-associated virus-mediated delivery of anti-pan amyloid beta, amyloid beta40, and amyloid beta42 single-chain variable fragments attenuates plaque pathology in amyloid precursor protein mice. J Neurosci, 26, 11923-8.
  • Kim J, Onstead L, Randle S, Price R, Smithson L, Zwizinski C, Dickson DW, Golde T, McGowan E. (2007) Abeta40 inhibits amyloid deposition in vivo. J Neurosci, 27, 627-33.
  • Kukar T. L., Ladd T. B., Bann M. A., Fraering P. C., Narlawar R., Maharvi G. M., Healy B., Chapman R., Welzel A. T., Price R. W., Moore B., Rangachari V., Cusack B., Eriksen J., Jansen-West K., Verbeeck C., Yager D., Eckman C., Ye W., Sagi S., Cottrell B. A., Torpey J., Rosenberry T. L., Fauq A., Wolfe M. S., Schmidt B., Walsh D. M., Koo E. H. and Golde T. E. (2008) Substrate-targeting gamma-secretase modulators. Nature 453, 925-929.
  • Kim J., Miller V. M., Levites Y., West K. J., Zwizinski C. W., Moore B. D., Troendle F. J., Bann M., Verbeeck C., Price R. W., Smithson L., Sonoda L., Wagg K., Rangachari V., Zou F., Younkin S. G., Graff-Radford N., Dickson D., Rosenberry T. and Golde T. E. (2008) BRI2 (ITM2b) inhibits abeta deposition in vivo. J Neurosci 28, 6030-6036.
  • Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C, Levites Y, Verbeeck C, Zubair AC, Dickson D, Golde TE, Das P (2009) Massive gliosis induced by interleukin-6 suppresses A{beta} deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. Faseb J.