University of Edinburgh Momentum Award – Dementias
Lead Research Organisation:
University of Edinburgh
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
Microglia, the resident macrophages of the central nervous system (CNS), and monocyte-derived cells are critical effectors and sculptors of changes in the CNS environment (1). In recent years, it has become clear that microglia and myeloid cells such as monocytes, macrophages, or dendritic cells are ontogenetically and also functionally distinct innate immune cell populations in the CNS. The goal of my research is to characterize the heterogeneity of CNS myeloid cells and to determine their differential functions in neurodegenerative diseases.
Using multiplexed single-cell mass cytometry (CyTOF), we have characterized the phenotypic signature of human microglia, which is distinct from myeloid cells in the cerebrospinal fluid and peripheral blood (2). Notably, we detected significant regional heterogeneity of human microglia. We are currently combining CyTOF with another high-dimensional technique (scRNA-seq) to investigate the context-specific adaptive responses of microglia during pathology. This approach will enable us to identify and characterize previously unknown microglia subsets in the human brain, their spatial distribution, and their changes with aging and neurodegeneration.
In a second line of research, we are establishing a novel CNS-conditioned in vitro model of human microglia using patient-derived induced pluripotent stem cells (iPSCs) in collaboration with Siddharthan Chandran’s group at the DRI. This approach will enable us to study the dynamic changes of microglia that occur in neurodegenerative diseases as a result of genetic mutations and environmental changes. It will also provide us with the opportunity to model the context-specific adaptive responses of microglia that we detect in the human brain, and to explore their potential pathogenetic relevance in neurodegenerative diseases.
We hope that the characterization of disease-associated microglia subtypes in the human CNS will open new avenues for subset-specific therapeutic interventions in neuropsychiatric disorders.
Using multiplexed single-cell mass cytometry (CyTOF), we have characterized the phenotypic signature of human microglia, which is distinct from myeloid cells in the cerebrospinal fluid and peripheral blood (2). Notably, we detected significant regional heterogeneity of human microglia. We are currently combining CyTOF with another high-dimensional technique (scRNA-seq) to investigate the context-specific adaptive responses of microglia during pathology. This approach will enable us to identify and characterize previously unknown microglia subsets in the human brain, their spatial distribution, and their changes with aging and neurodegeneration.
In a second line of research, we are establishing a novel CNS-conditioned in vitro model of human microglia using patient-derived induced pluripotent stem cells (iPSCs) in collaboration with Siddharthan Chandran’s group at the DRI. This approach will enable us to study the dynamic changes of microglia that occur in neurodegenerative diseases as a result of genetic mutations and environmental changes. It will also provide us with the opportunity to model the context-specific adaptive responses of microglia that we detect in the human brain, and to explore their potential pathogenetic relevance in neurodegenerative diseases.
We hope that the characterization of disease-associated microglia subtypes in the human CNS will open new avenues for subset-specific therapeutic interventions in neuropsychiatric disorders.
Publications
Böttcher C
(2020)
Single-cell mass cytometry reveals complex myeloid cell composition in active lesions of progressive multiple sclerosis
in Acta Neuropathologica Communications
Mueller SH
(2018)
Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis.
in Annals of neurology
Valdés Hernández MDC
(2019)
Structural neuroimaging differentiates vulnerability from disease manifestation in colombian families with Huntington's disease.
in Brain and behavior
Nickchen K
(2017)
Reversal learning reveals cognitive deficits and altered prediction error encoding in the ventral striatum in Huntington's disease.
in Brain imaging and behavior
Fernández-Zapata C
(2020)
The use and limitations of single-cell mass cytometry for studying human microglia function.
in Brain pathology (Zurich, Switzerland)
Fernandez-Klett F
(2020)
Denser brain capillary network with preserved pericytes in Alzheimer's disease.
in Brain pathology (Zurich, Switzerland)
Berchtold D
(2020)
Interaction of microglia with infiltrating immune cells in the different phases of stroke.
in Brain pathology (Zurich, Switzerland)
Ormel PR
(2020)
A characterization of the molecular phenotype and inflammatory response of schizophrenia patient-derived microglia-like cells.
in Brain, behavior, and immunity
Prinz M
(2019)
Microglia Biology: One Century of Evolving Concepts.
in Cell
Lorenz C
(2017)
Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders
in Cell Stem Cell
Mühlbäck A
(2020)
[Gene-selective treatment approaches for Huntington's disease].
in Der Nervenarzt
Munro DAD
(2020)
CNS macrophages differentially rely on an intronic Csf1r enhancer for their development.
in Development (Cambridge, England)
Zink A
(2020)
Assessment of Ethanol-Induced Toxicity on iPSC-Derived Human Neurons Using a Novel High-Throughput Mitochondrial Neuronal Health (MNH) Assay.
in Frontiers in cell and developmental biology
Andrade-Navarro MA
(2020)
RNA Sequencing of Human Peripheral Blood Cells Indicates Upregulation of Immune-Related Genes in Huntington's Disease.
in Frontiers in neurology
Mildner A
(2017)
Genomic Characterization of Murine Monocytes Reveals C/EBPß Transcription Factor Dependence of Ly6C - Cells
in Immunity
Onizawa H
(2021)
Aicardi-Goutières syndrome-like encephalitis in mutant mice with constitutively active MDA5.
in International immunology
Anderson KE
(2018)
Clinical Management of Neuropsychiatric Symptoms of Huntington Disease: Expert-Based Consensus Guidelines on Agitation, Anxiety, Apathy, Psychosis and Sleep Disorders.
in Journal of Huntington's disease
Zink A
(2018)
Pluripotent Stem Cells for Uncovering the Role of Mitochondria in Human Brain Function and Dysfunction.
in Journal of molecular biology
Martinez-Horta S
(2020)
Utility of the Parkinson's disease-Cognitive Rating Scale for the screening of global cognitive status in Huntington's disease.
in Journal of neurology
Snijders GJLJ
(2021)
Distinct non-inflammatory signature of microglia in post-mortem brain tissue of patients with major depressive disorder.
in Molecular psychiatry
Masuda T
(2019)
Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution.
in Nature
Ziegler JF
(2019)
Leptin induces TNFa-dependent inflammation in acquired generalized lipodystrophy and combined Crohn's disease.
in Nature communications
Rojo R
(2019)
Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations.
in Nature communications
Masuda T
(2020)
Novel Hexb-based tools for studying microglia in the CNS.
in Nature immunology
Priller J
(2017)
Patrolling monocytes sense peripheral infection and induce cytokine-mediated neuronal dysfunction.
in Nature medicine
Lloyd AF
(2019)
Central nervous system regeneration is driven by microglia necroptosis and repopulation.
in Nature neuroscience
Tay TL
(2017)
A new fate mapping system reveals context-dependent random or clonal expansion of microglia.
in Nature neuroscience
Prinz M
(2017)
The role of peripheral immune cells in the CNS in steady state and disease.
in Nature neuroscience
Sankowski R
(2019)
Mapping microglia states in the human brain through the integration of high-dimensional techniques.
in Nature neuroscience
Böttcher C
(2019)
Human microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometry.
in Nature neuroscience
Rolfes S
(2020)
Lentiviral delivery of human erythropoietin attenuates hippocampal atrophy and improves cognition in the R6/2 mouse model of Huntington's disease.
in Neurobiology of disease
Oosterloo M
(2019)
Clinical and genetic characteristics of late-onset Huntington's disease.
in Parkinsonism & related disorders
Cox ER
(2020)
Dialysis and plasmapheresis for schizophrenia: a systematic review.
in Psychological medicine
Priller J
(2019)
Targeting microglia in brain disorders.
in Science (New York, N.Y.)
Böttcher C
(2019)
Multi-parameter immune profiling of peripheral blood mononuclear cells by multiplexed single-cell mass cytometry in patients with early multiple sclerosis.
in Scientific reports
Banerjee P
(2020)
Generation of pure monocultures of human microglia-like cells from induced pluripotent stem cells.
in Stem cell research
Wieghofer P
(2021)
Mapping the origin and fate of myeloid cells in distinct compartments of the eye by single-cell profiling.
in The EMBO journal
Scior A
(2018)
Complete suppression of Htt fibrilization and disaggregation of Htt fibrils by a trimeric chaperone complex.
in The EMBO journal
Moss D
(2017)
Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study
in The Lancet Neurology
Reilmann R
(2019)
Safety and efficacy of pridopidine in patients with Huntington's disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study.
in The Lancet. Neurology
Böttcher C
(2020)
Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression.
in Translational psychiatry
Miron VE
(2020)
Investigating Microglia in Health and Disease: Challenges and Opportunities.
in Trends in immunology
Guideline Title | Chorea Leitlinie |
Description | EHDN |
Geographic Reach | Europe |
Policy Influence Type | Citation in clinical guidelines |
Impact | Treatment guideline for movement disorders |
Description | Neuropsychiatry Committee DGPPN |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Improvement in the services provided for patients with neuropsychiatric disorders, training and education in neuropsychiatry, establishment of national and international treatment guidelines |
Description | Update Neuropsychiatry DGPPN |
Geographic Reach | National |
Policy Influence Type | Influenced training of practitioners or researchers |
Impact | Annual workshops for medical care professionals at the DGPPN annual meetings |
Description | BIH Platform Humanized Model Systems |
Amount | € 35,000 (EUR) |
Organisation | Charité - University of Medicine Berlin |
Sector | Academic/University |
Country | Germany |
Start | 01/2019 |
End | 12/2019 |
Description | Peripheral monocytes for central nervous system remyelination |
Amount | £176,629 (GBP) |
Funding ID | C012-19.1 |
Organisation | Multiple Sclerosis Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2020 |
End | 12/2021 |
Description | SFB-TR167 B05,B07,IRTG |
Amount | € 10,600,000 (EUR) |
Organisation | German Research Foundation |
Sector | Charity/Non Profit |
Country | Germany |
Start | 01/2017 |
End | 12/2020 |
Description | CCBS, Prof. Chandran |
Organisation | University of Edinburgh |
Department | Centre for Clinical Brain Sciences (CCBS) |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Funding and supervision of PhD student, technician and postdoc, consumables, lab space |
Collaborator Contribution | Funding and supervision of staff, consumables |
Impact | Banerjee P, Paza E, Perkins EM, James OG, Kenkhuis B, Lloyd AF, Burr K, Story D, Yusuf D, He X, Backofen R, Dando O, Chandran S, Priller J. Generation of pure monocultures of human microglia-like cells from induced pluripotent stem cells. Stem Cell Res. 2020 Dec;49:102046. doi: 10.1016/j.scr.2020.102046. Munro DAD, Bradford BM, Mariani SA, Hampton DW, Vink CS, Chandran S, Hume DA, Pridans C, Priller J. CNS macrophages differentially rely on an intronic Csf1r enhancer for their development. Development. 2020 Dec 15;147(23):dev194449. doi: 10.1242/dev.194449. Banerjee P, Mehta AR, Nirujogi RS, Cooper J, James OG, Nanda J, Longden J, Burr K, McDade K, Salzinger A, Paza E, Newton J, Story D, Pal S, Smith C, Alessi DR, Selvaraj BT, Priller J*, Chandran S*. Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration. Sci Adv. 2023 Apr 21;9(16):eabq0651. doi: 10.1126/sciadv.abq0651. (*co-corresponding authors) Presentations at national conferences |
Start Year | 2017 |
Description | CDBS, Dr. Barry McColl |
Organisation | University of Edinburgh |
Department | Centre for Discovery Brain Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Supervision of staff, consumables, expertise |
Collaborator Contribution | Expertise , supervision of staff |
Impact | Shih BB, Brown SM, Barrington J, Lefevre L, Mabbott NA, Priller J, Thompson G, Lawrence AB, McColl BW. Defining the pig microglial transcriptome reveals its core signature, regional heterogeneity, and similarity with human and rodent microglia. Glia. 2023 Feb;71(2):334-349. doi: 10.1002/glia.24274. McNamara NB, Munro DAD, Bestard-Cuche N, Uyeda A, Bogie JFJ, Hoffmann A, Holloway RK, Molina-Gonzalez I, Askew KE, Mitchell S, Mungall W, Dodds M, Dittmayer C, Moss J, Rose J, Szymkowiak S, Amann L, McColl BW, Prinz M, Spires-Jones TL, Stenzel W, Horsburgh K, Hendriks JJA, Pridans C, Muramatsu R, Williams A, Priller J, Miron VE. Microglia regulate central nervous system myelin growth and integrity. Nature. 2023 Jan;613(7942):120-129. doi: 10.1038/s41586-022-05534-y. FENS educational symposium 2020 |
Start Year | 2017 |
Description | CDBS, Dr. Dirk Sieger |
Organisation | University of Edinburgh |
Department | Centre for Discovery Brain Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Funding and supervision of staff, consumables, equipment |
Collaborator Contribution | Co-supervision of staff, provision of lab equipment |
Impact | Chia K, Klingseisen A, Sieger D, Priller J. Zebrafish as a model organism for neurodegenerative disease. Front Mol Neurosci. 2022 Oct 13;15:940484. doi: 10.3389/fnmol.2022.940484. |
Start Year | 2018 |
Description | MRC Center for Regenerative Medicine, Prof. Williams |
Organisation | University of Edinburgh |
Department | MRC Centre for Regenerative Medicine |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Co-supervision of PhD student, provision of human biosamples, funding of sequencing costs, RNA-sequencing and bioinformatic analysis |
Collaborator Contribution | Lab space, expertise, consumables |
Impact | Lloyd AF, Davies CL, Holloway RK, Labrak Y, Ireland G, Carradori D, Dillenburg A, Borger E, Soong D, Richardson JC, Kuhlmann T, Williams A, Pollard JW, des Rieux A, Priller J, Miron VE. Central nervous system regeneration is driven by microglia necroptosis and repopulation. Nat Neurosci. 2019 Jul;22(7):1046-1052. doi: 10.1038/s41593-019-0418-z. McNamara NB, Munro DAD, Bestard-Cuche N, Uyeda A, Bogie JFJ, Hoffmann A, Holloway RK, Molina-Gonzalez I, Askew KE, Mitchell S, Mungall W, Dodds M, Dittmayer C, Moss J, Rose J, Szymkowiak S, Amann L, McColl BW, Prinz M, Spires-Jones TL, Stenzel W, Horsburgh K, Hendriks JJA, Pridans C, Muramatsu R, Williams A, Priller J, Miron VE. Microglia regulate central nervous system myelin growth and integrity. Nature. 2023 Jan;613(7942):120-129. doi: 10.1038/s41586-022-05534-y. Scientific presentations at conferences |
Start Year | 2019 |
Description | Microglia dynamics in CNS regeneration |
Organisation | University of Edinburgh |
Department | MRC Centre for Reproductive Health |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Provision of lab space, animal model and consumables |
Collaborator Contribution | PhD student performed experiments in my lab, established in vitro remyelination assay |
Impact | Lloyd et al., Nat Neuroscience (2019), thesis prize |
Start Year | 2017 |
Description | UK DRI and University of Toronto, Canada, Prof. Miron |
Organisation | University of Edinburgh |
Department | Queen's Medical Research Institute Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Co-supervision of students, scientific collaboration, consumables |
Collaborator Contribution | Co-supervision of students, consumables |
Impact | Lloyd AF, Davies CL, Holloway RK, Labrak Y, Ireland G, Carradori D, Dillenburg A, Borger E, Soong D, Richardson JC, Kuhlmann T, Williams A, Pollard JW, des Rieux A, Priller J, Miron VE. Central nervous system regeneration is driven by microglia necroptosis and repopulation. Nat Neurosci. 2019 Jul;22(7):1046-1052. doi: 10.1038/s41593-019-0418-z. Miron VE, Priller J. Investigating Microglia in Health and Disease: Challenges and Opportunities. Trends Immunol. 2020 Sep;41(9):785-793. doi: 10.1016/j.it.2020.07.002. Michelucci A, Miron VE, Priller J. Special Issue "Microglia Heterogeneity and Its Relevance for Translational Research". Int J Mol Sci. 2021 Nov 16;22(22):12350. doi: 10.3390/ijms222212350. McNamara NB, Munro DAD, Bestard-Cuche N, Uyeda A, Bogie JFJ, Hoffmann A, Holloway RK, Molina-Gonzalez I, Askew KE, Mitchell S, Mungall W, Dodds M, Dittmayer C, Moss J, Rose J, Szymkowiak S, Amann L, McColl BW, Prinz M, Spires-Jones TL, Stenzel W, Horsburgh K, Hendriks JJA, Pridans C, Muramatsu R, Williams A, Priller J*, Miron VE*. Microglia regulate central nervous system myelin growth and integrity. Nature. 2023 Jan;613(7942):120-129. doi: 10.1038/s41586-022-05534-y. (*equal contribution) |
Start Year | 2017 |
Title | EGCG in Huntington"s disease |
Description | Phase 2 randomised, placebo-controlled, multi-centre trial on 1200 mg EGCG/day in patients with Huntington's disease, IIT (DFG funding) |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Early clinical assessment |
Year Development Stage Completed | 2015 |
Development Status | Closed |
Clinical Trial? | Yes |
Impact | Pharmacokinetic data in HD patients |
URL | https://clinicaltrials.gov/show/NCT01357681 |
Description | EHDN |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Lead facilitator in Working Group on Symptomatic Treatment and Research |
Year(s) Of Engagement Activity | Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016,2017,2018 |
Description | Extended Board member, DGGPP |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | German Society for Geriatric Psychiatry |
Year(s) Of Engagement Activity | 2019,2020 |
Description | Interview for national news (Spiegel, Welt am Sonntag) |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Explanation of clinical trial results |
Year(s) Of Engagement Activity | 2017,2018 |
Description | Neuropsychiatry Committee DGPPN |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Chair of the Neuropsychiatry Committee, DGPPN |
Year(s) Of Engagement Activity | 2011,2012,2013,2014,2015,2016,2017,2018 |