Mechanisms of neuronal loss in dementia: Role of matrix metalloproteinases in the degradation of the perineuronal net

The development of effective treatments for neurodegenerative diseases associated with dementia requires an understanding of the pathological processes underlying nerve cell (neuron) loss. Normally, neurons are set within the extracellular matrix (ECM) of the brain– a glue-like structure that can be actively remodelled. Immediately around the neuron this ECM forms a protective scaffold called the perineuronal net (PN). Removal of particular components of the PN results in an inability of neurons to function normally.
We have shown that PN loss occurs is an early pathological feature of neurodegeneration. This is found in association with abnormal functioning of neurons and an abnormality of learning and memory. The actual loss of neurons is a late feature of the disease. There is therefore a period of time when targeted treatment(s) may prevent neuronal loss and the debilitating symptoms associated with it. This study will investigate the mechanism of PN loss and will provide insights into the development of treatments to prevent it.

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.