Exploring glial-neuronal interactions at the transition from brain vulnerability to pathology

Lead Research Organisation: Imperial College London

Abstract

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Technical Summary

The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Funding details for UK DRI programmes will be added in 2019.

Glial activation is associated with the earliest neuronal dysfunction in models of neurodegenerative disease and in human disease post mortem (1). Some of these changes are maladaptive, contributing to network dysfunction. For example, microglial activation is associated with excessive synaptic stripping (2), changes in excitation-inhibition balance, increased microcircuit excitability and early neuronal network dysfunction (3). Pro-inflammatory activated microglia induce a subtype of reactive astrocytes likely contributing to neuronal death in neurodegenerative disorders (4). However, glia also have important homeostatic and neuroprotective roles (3, 5). The complex phenotypes of glial cells, their interactions, and temporal evolution thus need to be understood to discover ways of modulating biasing them towards neuroprotective phenotypes. Microglia play a central role in coordinating homeostatic responses of the glial unit to integrated environmental and neuronal signals, e.g., for balancing amyloid clearance with neuronal activity in the healthy brain (6, 7). Microglial proliferation and activation are amongst the earliest changes in the progression of neurodegenerative pathologies associated with amyloid (and in other neurodegenerative contexts). Understanding microglial homeostatic mechanisms and their failure will provide both insights into neurodegenerative mechanisms and novel concepts for slowing or reversing early disease. My group has been applying a range of imaging, genomic and chemical methods to address homeostatic roles of microglia in the inflammatory neurodegenerative processes of multiple sclerosis and in normal aging (e.g.,
(8-11)). Methodological advances and a unique cluster of expertise in my group and with close collaborators at Imperial puts us in an ideal position to re-address fundamental questions:

• What molecular changes in microglia are associated with early neuronal network homeostasis and
• dysfunction in amyloid models?
• What chemical signals between glia and neurons mediate this?
• How does neuronal activity change the microglial phenotype (and vice versa)?
• We have extensively employed in vivo imaging, which has highlighted the dynamics

Publications

10 25 50
 
Description Biogen REM2 snRNASeq Collaboration 
Organisation Biogen Idec
Country United States 
Sector Private 
PI Contribution Ascertainment and sequencing of nuclei from TREM2var brains
Collaborator Contribution Bioinformatics for snRNASeq analysis
Impact Pending
Start Year 2019
 
Description Nodthera Inflammasome Collaboration 
Organisation NodThera
Country United Kingdom 
Sector Private 
PI Contribution Assessment of novel potential therapeutics
Collaborator Contribution Joint development of research design
Impact None yet
Start Year 2018
 
Description Lecture on science behind creativity for lay audience 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Participation in workshop on creativity
Year(s) Of Engagement Activity 2019
URL https://www.seh.ox.ac.uk/discover/research/centre-for-the-creative-brain-2