Role of IFNGR1 in reactive astrocyte activation
Award Number
BB/V006444/1Status / Stage
ActiveDates
4 January 2021 -3 October 2024
Duration (calculated)
03 years 08 monthsFunder(s)
BBSRC (UKRI)Funding Amount
£560,720.00Funder/Grant study page
BBSRC UKRIContracted Centre
University of EdinburghPrincipal Investigator
Professor Neil MabbottPI Contact
neil.mabbott@roslin.ed.ac.ukPI ORCID
0000-0001-7395-1796WHO Catergories
Understanding Underlying DiseaseDisease Type
Dementia (Unspecified)CPEC Review Info
| Reference ID | 734 |
|---|---|
| Researcher | Reside Team |
| Published | 07/07/2023 |
Data
| Award Number | BB/V006444/1 |
|---|---|
| Status / Stage | Active |
| Start Date | 20210104 |
| End Date | 20241003 |
| Duration (calculated) | 03 years 08 months |
| Funder/Grant study page | BBSRC UKRI |
| Contracted Centre | University of Edinburgh |
| Funding Amount | £560,720.00 |
Abstract
Astrocytes are important glial cells in the brain that provide homeostatic support to neurons in the steady state, but can undergo reactive astrocytosis after brain injury and during neurodegeneration. Little is known of the mechanisms underpinning these properties, but microglial-derived TNF, IL-1a and complement C1q can induce neurotoxic astrocytes. Our data show that interferon-gamma receptor 1 (IFNGR1) is highly expressed by reactive astrocytes during neurodegeneration. Furthermore, a systemic Th1-polarized IFN-gamma-mediated inflammatory response induced by an intestinal pathogen co-infection enhances the neurotoxic profile of IFNGR1+ astrocytes, accelerating neurodegeneration. IFNGR1+ astrocytes also occur in the aging human brain and in patients with other neurodegenerative diseases, suggesting that IFNGR1 signalling is an important mediator of neurotoxic astrocyte activation. Little is known of the in vivo phenotype of IFNGR1+ astrocytes. Our previous data show that neuropathology during CNS prion disease is unaffected in TNFa-/- and C1q-/- mice indicating that other microglial-derived stimuli induce IFNGR1+ reactive astrocytes. This study will address these important knowledge gaps and test the hypothesis that IFNGR1 signalling is a key mediator of neurotoxic reactive astrocyte activation. The main aims are to determine: 1, the microglia-derived factors that are required for the induction and maintenance of IFNGR1+ reactive astrocytes; 2, the phenotype of INFGR1+ reactive astrocytes; 3, whether astrocyte-specific IFNGR1-signalling accelerates neurodegeneration in vivo. Data from this study will have widespread application. This study may help identify novel treatments to counteract the adverse effects of systemic IFN-gamma responses (eg: during systemic/intestinal pathogen infections) on the progression of some neurodegenerative diseases. These data may also aid development of new methods to help counteract the adverse effects of aging on the brain.
Aims
The main aims are to determine: 1, the microglia-derived factors that are required for the induction and maintenance of IFNGR1+ reactive astrocytes; 2, the phenotype of INFGR1+ reactive astrocytes; 3, whether astrocyte-specific IFNGR1-signalling accelerates neurodegeneration in vivo.