Mechanisms of neuronal loss in dementia: Role of matrix metalloproteinases in the degradation of the perineuronal net
Award Number
G0700425Status / Stage
CompletedDates
1 August 2008 -14 October 2011
Duration (calculated)
03 years 02 monthsFunder(s)
MRC (UKRI)Funding Amount
£490,080.00Funder/Grant study page
MRC UKRIContracted Centre
University of BradfordPrincipal Investigator
Dr Betmouni, SWHO Catergories
Understanding risk factorsUnderstanding Underlying Disease
Disease Type
Dementia (Unspecified)CPEC Review Info
| Reference ID | 280 |
|---|---|
| Researcher | Reside Team |
| Published | 12/06/2023 |
Data
| Award Number | G0700425 |
|---|---|
| Status / Stage | Completed |
| Start Date | 20080801 |
| End Date | 20111014 |
| Duration (calculated) | 03 years 02 months |
| Funder/Grant study page | MRC UKRI |
| Contracted Centre | University of Bradford |
| Funding Amount | £490,080.00 |
Abstract
The applicant has a longstanding collaboration with Dr Greeene (MRC Centre for Synaptic Plasticity, University of Bristol)investigating the relationships between abnormal behaviour, altered electrophysiological properties of neurons and circuits, and neuropathological changes in neurodegenerative conditions using murine prion disease as our experimental paradigm. We have produced a very detailed, and fully integrated, description of murine prion disease (ME7)and found that well before either clinical signs or neuronal loss, there are abnormalities of hippocampus-dependent behaviour; reduced long term potentiation (LTP)in hippocampal slices; disruption of the perineuronal net (PN)- a specialised extracellular matrix (ECM)that surrounds neurons, CNS inflammation, and increased levels of specific matrix metalloproteinases (MMPs). MMPs are a family of enzymes that degrade the ECM and which are over expressed in several human neurodegenerative conditions. The purpose of this application is to further test the working hypothesis we have developed that early in the course of this chronic neurodegenerative process there is activation of MMPs which then degrade the PN. The project will combine molecular biological and histological techniques to test the following hypotheses; 1. MMP expression occurs early in the course of murine prion disease, 2. MMP expression and activity precedes PN loss in murine prion disease, 3. MMP3 degrades the PN in vivo. We believe that these pathogenic processes occur prior to irreversible changes, such as neuronal loss. Furthermore, we believe that these processes will be common to other, more common, neurodegenerative diseases, and as such are important targets for therapeutic interventions.
Aims
The project will combine molecular biological and histological techniques to test the following hypotheses; 1. MMP expression occurs early in the course of murine prion disease, 2. MMP expression and activity precedes PN loss in murine prion disease, 3. MMP3 degrades the PN in vivo.