Todd E Golde
Professor, Director McKnight Brain Institute
About Todd E Golde
Todd E. Golde, M.D., Ph.D., is director of the Evelyn F. and William L. McKnight Brain Institute (MBI) of the University of Florida, where he oversees, champions and facilitates neuroscience and neuromedicine research programs across the UF campus. A professor of neuroscience and neurology, Dr. Golde joined the UF faculty in 2009 and became founding director of UF’s Center for Translational Research in Neurodegenerative Disease (CTRND), which he led until taking the helm at the MBI in December 2016.
An internationally known expert in the scientific understanding of Alzheimer’s disease (AD), Dr. Golde has published more than 290 papers that have been cited more than 36,000 times. Over time his research has taken on a more transnational focus. He currently directs i) the NIH funded 1Florida Alzheimer’s Disease Research Center (ADRC, https://1floridaadrc.org/) that focuses on early detection and markers of progression in in diverse populations (especially Hispanics an African Americans) ii) a consortium U01 under the NIH’s accelerating medicine partnership AD program (AMP-AD) designed to identify novel targets in the immune systems in AD iii) studies exploring a novel immunotherapy targeting the HPA axis in AD , iv) the use of a novel brain slice culture model of tauopathy and α-synucleinopathy to identify therapeutic targets for the proteinopathies and the dysfunction that they cause, and v) an gene therapy approach to treating trigmenal neuralgia. Underlying his laboratory’s wet-bench research studies is the development of an extensive rAAV vector “toolkit” that enables us to accelerate translational preclinical studies that can help advance therapeutic discovery in many disease settings.
In addition to his research and intramural administrative activities, in recent years Dr. Golde has been an active advocate for AD and neurodegenerative disease research at the state, national and international levels. At the national level, he has served on the medical and scientific advisory board for the National Alzheimer’s Association and he continue to do so for the Bright Focus Foundation. At the state level, he has served on several advisory boards relating to AD, and has worked to secure state support for Alzheimer’s research at UF as well as implement a statewide grants program to support AD research. Through his scientific reviews and presentations at national and international conferences, he not only discuss scientific advances, but also highlight the many challenges that we face in combating the AD epidemic (see, for example, Golde et al Alz Res & Therapy 2011, Golde et al Neuron 2011, Golde J. Neurochemistry 2016, Golde et al. Science 2018, Dawson et al Nature Neuroscience 2018, Golde, Neuron 2019).
Accomplishments
Research Profile
CONTRIBUTIONS TO SCIENCE 1. As a MD PhD student and postdoc with Dr. Steven Younkin, I played a pivotal role in studies showing that the amyloid beta protein (Abeta) was a normal metabolite and that mutations that cause AD alter Abeta production in a manner that promote Abeta aggregation. These studies provided pivotal support for the Abeta aggregate (amyloid) hypothesis of AD and enabled drug discovery programs aimed at altering Abeta accumulation. a) Golde TE, Estus S, Younkin LH, Selkoe DJ, Younkin SG. Processing of the amyloid protein precursor to potentially amyloidogenic derivatives. Science. 1992;255(5045):728-30. doi: 10.1126/science.1738847. PubMed PMID: 1738847. b) Shoji M*, Golde TE*, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai XD, McKay DM, Tintner R, Frangione B. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992;258(5079):126-9. doi: 10.1126/science.1439760. PubMed PMID: 1439760.. c) Cai XD, Golde TE, Younkin SG. Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science. 1993;259(5094):514-6. doi: 10.1126/science.8424174. PubMed PMID: 8424174. d) Suzuki N, Cheung TT, Cai XD, Odaka A, Otvos L, Eckman C, Golde TE, Younkin SG. An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science. 1994;264(5163):1336-40. doi: 10.1126/science.8191290. PubMed PMID: 8191290. 2. In studies conducted in collaboration with Dr. Edward Koo’s laboratory (UCSD), we demonstrated that select non-steroidal anti-inflammatory agents (NSAIDs) could modulate Abeta42 production and that this effect was attributable to direct alteration of gamma-secretase activity. Subsequently we identified compounds that lowered Abeta42 but lacked cyclooxygenase activity, we also described compounds with the opposite effect that raise Aβ42 levels, and finally that these compounds work in part by targeting substrate. These data and modeling studies on the biological properties of “short” Aβ peptides has supported the rationale for development and testing of what are now referred to as gamma-secretase modulators (GSMs) as potential therapeutics for AD. a) 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. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature. 2001;414(6860):212-6. doi: 10.1038/35102591. PubMed PMID: 11700559. b) 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. Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production. Nat Med. 2005;11(5):545-50. Epub 2005/04/17. doi: 10.1038/nm1235. PubMed PMID: 15834426. c) Kukar TL, Ladd TB, Bann MA, Fraering PC, Narlawar R, Maharvi GM, Healy B, Chapman R, Welzel AT, Price RW, Moore B, Rangachari V, Cusack B, Eriksen J, Jansen-West K, Verbeeck C, Yager D, Eckman C, Ye W, Sagi S, Cottrell BA, Torpey J, Rosenberry TL, Fauq A, Wolfe MS, Schmidt B, Walsh DM, Koo EH, Golde TE. Substrate-targeting gamma-secretase modulators. Nature. 2008;453(7197):925-9. doi: 10.1038/nature07055. PubMed PMID: 18548070; PMCID: PMC2678541. d) Moore BD, Martin J, de Mena L, Sanchez J, Cruz PE, Ceballos-Diaz C, Ladd TB, Ran Y, Levites Y, Kukar TL, Kurian JJ, McKenna R, Koo EH, Borchelt DR, Janus C, Rincon-Limas D, Fernandez-Funez P, Golde TE. Short Aβ peptides attenuate Aβ42 toxicity in vivo. J Exp Med. 2018;215(1):283-301. Epub 2017/12/05. doi: 10.1084/jem.20170600. PubMed PMID: 29208777; PMCID: PMC5748850.3. 3. A parallel area of interest to GSMs has been the therapeutic utility of targeting intramembrane cleaving proteases in a variety of indications. In 2002, in collaboration with Dr. Chris Ponting, we identified a family of intramembrane protease (presenilin homologs/signal peptide peptidases) that was related to gamma-secretase. In work conducted in collaboration with Drs. Osborne (UMASS), Miele (LSU/Tulane), and Greenbaum (U Penn), we have evaluated targeting these proteases in cancer, immunologic disease, and malaria. a) Ponting CP, Hutton M, Nyborg A, Baker M, Jansen K, Golde TE. Identification of a novel family of presenilin homologues. Hum Mol Genet. 2002;11(9):1037-44. doi: 10.1093/hmg/11.9.1037. PubMed PMID: 11978763. b) Das P, Verbeeck C, Minter L, Chakrabarty P, Felsenstein K, Kukar T, Maharvi G, Fauq A, Osborne BA, Golde TE. Transient pharmacologic lowering of Aβ production prior to deposition results in sustained reduction of amyloid plaque pathology. Mol Neurodegener. 2012;7:39. Epub 2012/08/14. doi: 10.1186/1750-1326-7-39. PubMed PMID: 22892055; PMCID: PMC3477045. c) R Harbut MB, Patel BA, Yeung BK, McNamara CW, Bright AT, Ballard J, Supek F, Golde TE, Winzeler EA, Diagana TT, Greenbaum DC. Targeting the ERAD pathway via inhibition of signal peptide peptidase for antiparasitic therapeutic design. Proc Natl Acad Sci U S A. 2012;109(52):21486-91. Epub 2012/12/11. doi: 10.1073/pnas.1216016110. PubMed PMID: 23236186; PMCID: PMC3535666. d) Ran Y, Hossain F, Pannuti A, Lessard CB, Ladd GZ, Jung JI, Minter LM, Osborne BA, Miele L, Golde TE. γ-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. EMBO Mol Med. 2017;9(7):950-66. doi: 10.15252/emmm.201607265. PubMed PMID: 28539479; PMCID: PMC5494507. 4. My laboratory has been at the forefront of developing rAAV-based models and delivery of biotherapeutics to the brain, spinal cord and muscle. Much of this work has focused on delivery of potentially biotherapeutic molecules to models of Alzheimer’s disease. We continue to revise and update this technology, and our most recent study describes using minimally purified rAAV for both in vitro and ex vivo studies, which will enable rAAV technology to be much more accessible to the wider community. a) Levites Y, Jansen K, Smithson LA, Dakin R, Holloway VM, Das P, Golde TE. 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. 2006;26(46):11923-8. doi: 10.1523/JNEUROSCI.2795-06.2006. PubMed PMID: 17108166; PMCID: PMC6674861. b) Chakrabarty P, Rosario A, Cruz P, Siemienski Z, Ceballos-Diaz C, Crosby K, Jansen K, Borchelt DR, Kim JY, Jankowsky JL, Golde TE, Levites Y. Capsid serotype and timing of injection determines AAV transduction in the neonatal mice brain. PLoS One. 2013;8(6):e67680. Epub 2013/06/25. doi: 10.1371/journal.pone.0067680. PubMed PMID: 23825679; PMCID: PMC3692458. c) Ayers JI, Fromholt S, Sinyavskaya O, Siemienski Z, Rosario AM, Li A, Crosby KW, Cruz PE, DiNunno NM, Janus C, Ceballos-Diaz C, Borchelt DR, Golde TE, Chakrabarty P, Levites Y. Widespread and efficient transduction of spinal cord and brain following neonatal AAV injection and potential disease modifying effect in ALS mice. Mol Ther. 2015;23(1):53-62. Epub 2014/09/17. doi: 10.1038/mt.2014.180. PubMed PMID: 25228069; PMCID: PMC4426802. d) Goodwin MS, Croft CL, Futch HS, Ryu D, Ceballos-Diaz C, Liu X, Paterno G, Mejia C, Deng D, Menezes K, Londono L, Arjona K, Parianos M, Truong V, Rostonics E, Hernandez A, Boye SL, Boye SE, Levites Y, Cruz PE, Golde TE. Utilizing minimally purified secreted rAAV for rapid and cost-effective manipulation of gene expression in the CNS. Mol Neurodegener. 2020;15(1):15. Epub 2020/03/02. doi: 10.1186/s13024-020-00361-z. PubMed PMID: 32122372; PMCID: PMC7053119. 5. Over the last 10 years, my research has expanded into the area of innate immunity’s role in neurodegenerative disease. Recent work from my lab has challenged a long-standing hypothesis that inflammatory processes in AD accelerate Aβ deposition. Published studies also reveal a potential novel role of interferon-gamma in nigrostriatal degeneration and novel roles for decoy receptors in AD. We have now expanded these studies to broadly explore immune modulators as mediators of neurodegenerative pathways. a) Chakrabarty P, Jansen-West K, Beccard A, Ceballos-Diaz C, Levites Y, Verbeeck C, Zubair AC, Dickson D, Golde TE, Das P. Massive gliosis induced by interleukin-6 suppresses Abeta deposition in vivo: evidence against inflammation as a driving force for amyloid deposition. FASEB J. 2010;24(2):548-59. Epub 2009/10/13. doi: 10.1096/fj.09-141754. PubMed PMID: 19825975; PMCID: PMC3083918. b) Chakrabarty P, Ceballos-Diaz C, Lin WL, Beccard A, Jansen-West K, McFarland NR, Janus C, Dickson D, Das P, Golde TE. Interferon-γ induces progressive nigrostriatal degeneration and basal ganglia calcification. Nat Neurosci. 2011;14(6):694-6. Epub 2011/05/15. doi: 10.1038/nn.2829. PubMed PMID: 21572432; PMCID: PMC3780582. c) Chakrabarty P, Li A, Ladd TB, Strickland MR, Koller EJ, Burgess JD, Funk CC, Cruz PE, Allen M, Yaroshenko M, Wang X, Younkin C, Reddy J, Lohrer B, Mehrke L, Moore BD, Liu X, Ceballos-Diaz C, Rosario AM, Medway C, Janus C, Li HD, Dickson DW, Giasson BI, Price ND, Younkin SG, Ertekin-Taner N, Golde TE. TLR5 decoy receptor as a novel anti-amyloid therapeutic for Alzheimer’s disease. J Exp Med. 2018;215(9):2247-64. doi: 10.1084/jem.20180484. PubMed PMID: 30158114; PMCID: PMC6122970. d) Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, DiNunno N, Rosario AM, Cruz PE, Verbeeck C, Sacino A, Nix S, Janus C, Price ND, Das P, Golde TE. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron. 2015;85(3):519-33. Epub 2015/01/22. doi: 10.1016/j.neuron.2014.11.020. PubMed PMID: 25619653; PMCID: PMC4320003.
0000-0003-1867-7071
- Adeno-Associated Viral Gene Therapy
- Alzheimer’s Disease
- Cancer Therapeutics
- Dementia
- Immunoproteostasis
- Neurodegenerative diseases
- Neuroimmune interactions in Neurodegenerative diseases
- Trigeminal Neuralgia
- intramembrane cleaving proteases
Publications
Grants
Patents
Education
Contact Details
- Business:
- (352) 273-9456
- Business:
- tgolde@ufl.edu