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UK Dementia Research Institute at UCL

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Dr Soyon Hong

Programme lead: "Microglia-synapse biology in brain homeostasis and pathology"

Research summary

Microglia, the resident immune cells of the central nervous system, are active participants in brain wiring. They sculpt and refine neural circuits, and influence synaptic development and function. 

Dr Soyon Hong
However, remarkably little is known about how microglia communicate with neurons and whether microglia contribute to circuit-specific function in the adult brain.  Furthermore, emerging literature suggests diverse states of microglia, raising the need to understand what functional states microglia assume, and whether there is a region- or circuit-specific microglial heterogeneity that underlies brain wiring and function in the healthy brain and vulnerability to dysfunction and loss in the diseased brain. Altogether, my research aims to unravel the immune mechanisms of neural circuitry and function. The two arms of my laboratory will be to study how microglia impact circuit-specific function or behavior and to understand the immune basis of region-specific vulnerability in disease. Specifically, I am interested in understanding whether and how microglia contribute to higher cognitive functions such as learning and memory, and to region-specific vulnerability of synapse loss in neurologic diseases such as Alzheimer’s and Parkinson’s diseases. 

Teaching summary

I have mentored and taught many students and technicians through lectures and laboratory settings (11 mentees in laboratory settings to date). I highly value the opportunities to mentor. It is one aspect of my career that I find truly rewarding. I believe that having a positive, stimulating environment where trainees are valued is key to having a productive and creative lab. Trainees who join my laboratory will be trained in cellular and molecular biology including neuroscience and neuroimmunology. Moreover, they will be mentored to be independent critical thinkers, a core of my teaching philosophy.


Education

University of Washington, B.S. with distinction in Biochemistry, 2003

Harvard University, Ph.D. in Neuroscience, 2012



Biography

Dr. Hong received her PhD in Neuroscience in 2012 from Harvard University and completed her postdoctoral fellowship at Boston Children’s Hospital and Harvard Medical School in 2018. Dr. Hong is dedicated to the studying of microglia biology and mechanisms of neurodegeneration.  She studied microglia biology in health and disease (ALS, stroke) models with Drs. Thomas Möller and Michel Kliot at the University of Washington from 2002-2006, mechanisms of β-amyloid synaptotoxicity in Alzheimer mouse models with Dr. Dennis Selkoe at Harvard University from 2007-2012, and microglia-synapse interactions with Dr. Beth Stevens at Boston Children’s Hospital from 2012-2018. Dr. Hong’s laboratory aims to unravel the immune mechanisms of neural circuitry and function. Specifically, the laboratory is dedicated to investigating changes in microglial state and function in learning and memory, and how neuroglial communications break down in dementia. 


Vision for UK DRI programme

Recent genome-wide studies implicate microglia and immune-related pathways in Alzheimer’s disease (AD); however, biological significance of these immune pathways is not well understood. Interestingly, it is becoming increasingly clear that microglia are active partners in brain wiring, in that they help shape the developing brain and aid the breakdown of synaptic circuitry in disease. Loss of synaptic integrity is a hallmark of AD and several other neurologic diseases. My study as a postdoctoral fellow was among the first of a series of publications that suggest microglia as critical players in synaptic pathology in various disease models. Altogether, these findings raise the need to understand the immune basis of neurologic function and circuitry. Several questions have emerged: Do microglia specifically phagocytose dysfunctional synapses? What cues regulate microglial pruning? What molecules, besides complement, are utilized in neuroglial communication? The pathological functions of microglia reveal a need to fully understand what microglia do in the healthy adult brain and how they become dysfunctional with, or contribute to, aging and dementia.

In my laboratory, I aim to address these questions from several unique angles. First, I will investigate molecular pathways that target synapses for elimination in Alzheimer’s and Parkinson’s disease models and determine whether microglia confer region-specific synaptic and neuronal dysfunction. Second, I will study whether and how microglia contribute to higher cognitive functions, i.e. learning and memory. Third, I am interested in understanding how adaptive immune signaling contributes to neuroglial interactions in the adult brain.  I will study this in the context of normal aging and neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease mouse models.  The experiments I propose will broaden our understanding of how different cell types work together to maintain brain function, and how these interactions may go awry during aging and dementia. Furthermore, they have the goal of being extended into translational research relevant to humans. As region-specific vulnerability is a hallmark of many neurodegenerative diseases, my proposed experiments have the potential to reveal mechanistic insight in a variety of neurologic diseases.

Publications
  1. Hong S & Stevens B. TREM2: keeping microglia fit during good times and bad. Cell Metabolism. 2017 Oct 3;26(4):590-591.
  2. Shi Q, Chowdhury S, Ma R, Le KX, Hong S, Caldarone BJ, Stevens B & Lemere CA. Complement C3-deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Science Translation Medicine. 2017 May1 31;9(392).
  3. Hong S, Wilton D, Stevens B & Richardson D. Structured illumination microscopy for the investigation of synaptic structure and function. Methods in Molecular Biology; Synapse Development: Methods and Protocols. 2017 1538:155-167. PMC5479421.
  4. Hong S & Stevens B. Microglia: phagocytosing to clear, sculpt and eliminate. Developmental Cell. 2016 Jul 25;38(2):126-8.
  5. Hong S, Nfonoyim BM, Beja-Glasser VF, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ & Stevens B. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016 May 6;352(6286):712-6. PMC5094372. Epub 2016 Mar 31.
  6. Hong S, Dissing-Olesen L & Stevens B. New insights on the role of microglia in synaptic pruning in health & disease. Current Opinion in Neurobiology. 2016 Feb;36:128-34. PMC5479435.
  7. Chen AC, Kim S, Shepardson N, Patel S, Hong S & Selkoe DJ. Physical and functional interaction between the α- and γ-secretases: a new model of regulated intramembrane proteolysis. Journal of Cellular Biology. 2015 Dec 21;211(6):1157-76. PMC4687875.
  8. Dissing-Olesen L, Hong S & Stevens B. New brain lymphatic vessels drain old concepts. EBioMedicine. 2015 Aug 14;2(8):776-7. PMC4563157.
  9. Shi Q, Colodner KJ, Matousek SB, Merry KM, Hong S, Kenison JE, Frost JL, Le K, Li S, Dodart JC, Caldarone BJ, Stevens B & Lemere CA. Complement C3-deficient mice fail to display age-related hippocampal decline. Journal of Neuroscience. 2015 Sep 23;35(38):13029-42.
  10. Hong S, Ostaszewski BL, Yang T, O’Malley TT, Jin M, Yanagisawa K, Li S, Bartels T & Selkoe DJ. Soluble Aβ oligomers are rapidly sequestered from brain ISF in vivo and bind GM1 ganglioside on cellular membranes. Neuron. 2014 Apr 16;82(2):308-19. PMC4129520. Epub 2014 Mar 27.
  11. Yang T, Hong S, O’Malley T, Sperling RA, Walsh DM & Selkoe DJ. ELISAs with high specificity for soluble oligomers of amyloid β-protein detect natural Aβ oligomers in human brain but not CSF. Alzheimers Dement. 2013 Mar;9(2):99-112. PMC3604133. Epub 2013 Jan 30.
  12. Fu H, Liu B, Frost JL, Hong S, Jin M, Ostaszewski BL, Shankar GM, Costantino I, Carroll M, Mayadas T and Lemere CA. Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Aβ by microglia. Glia. 2012 May;60(6):993-1003. PMC3325361. Epub 2012 Mar 21.
  13. Hong S, Quintero-Monzon O, Ostaszewski BL, Podlisny DR, Yang T, Holtzman DM, Cirrito JR & Selkoe DJ. Dynamic analysis of amyloid β-protein in behaving mice reveals opposing changes in ISF vs. parenchymal Aβ during age-related plaque formation. Journal of Neuroscience. 2011 Nov 2;31(44):15861-9. PMC3227224.
  14. Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM & Selkoe DJ. Soluble oligomers of amyloid β-protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron. 2009 Jun 25;62(6):788-801. PMC2702854.
  15. Nazer, B, Hong S and Selkoe DJ. LRP promotes endocytosis and degradation, but not transcytosis, of the amyloid- beta peptide in a blood-brain barrier in vitro model. Neurobiology of Disease. 2008 Apr;30(1):94-102. PMC2376120.
  16. Giorgini F, Möller T, Kwan W, Zwilling D, Wacker JL, Hong S, Tsai LC, Cheah CS, Schwarcz R, Guidetti P & Muchowski PJ. Histone deacetylase inhibition modulates kynurenine pathway activation in yeast, microglia, and mice expressing a mutant huntingtin fragment. Journal of Biological Chemistry. 2008 Mar 21;283(12):7390-400. Epub 2007 Dec 13.
  17. Weinstein JR*, Hong S*, Kulman JD, Bishop C, Kuniyoshi J, Andersen H, Ransom BR, Hanisch UK & Möller T. Unraveling thrombin’s true microglia-activating potential: markedly disparate profiles of pharmaceutical-grade and commercial-grade thrombin preparations. Journal of Neurochemistry. 2005 Nov;95(4):1177-87.
  18. Weydt P*, Hong S*, Witting A, Möller T, Stella N & Kliot M. Cannabinol delays symptom onset in SOD1 (G93A) transgenic mice without affecting survival. ALS and Other Motor Neuron Disorders. 2005 Sep;6(3):182-4.
  19. Witting A, Weydt P, Hong S, Kliot M, Möller T & Stella N. Endocannabinoids accumulate in the spinal cord of SOD1 G93A transgenic mice. Journal of Neurochemistry. 2004 Jun;89(6):1555-7. doi: 10.1111/j.1471-4159.2004.02544.x.
  20. Weydt P*, Hong SY*, Kliot M & Möller T. Assessing disease onset and progression in the SOD1 mouse model of ALS. Neuroreport. 2003 May 23;14(7):1051-4.

*Co-first author