The Vascular Dementia (VaD) Matrix Project

 
 

We are a consortium of researchers from the universities of Edinburgh, Glasgow, Manchester, Oxford and Cambridge investigating the hypothesis that risk factors for small vessel disease cause extracellular matrix defects resulting in the disruption of the neurogliovascular unit, leading to the development of small vessel disease and vascular cognitive impairment.

Cerebral small vessel disease (SVD) is a leading cause of vascular cognitive impairment and dementia. Despite its importance there are few treatments for established disease, a situation hindered by a lack of understanding of disease mechanisms. A complex interaction between environmental and genetic risk factors are at play in the pathogenesis of SVD but the underlying molecular basis of these processes remains to be defined.

It is proposed that central to SVD pathophysiology is the disruption of the finely tuned interplay between the cells of neurogliovascular unit (NGVU). The NGVU forms and maintains the blood brain barrier (BBB), controlling the exchange of substances between blood and brain. Work, including previous publications for this group, has highlighted several important and common pathogenic features of NGVU disruption in SVD, including, myelin damage, microvascular inflammation, gliovascular disruption and BBB breakdown.

While the underlying mechanisms are unknown, central to maintaining NGVU integrity is the basement membrane/extracellular matrix complex. The ECM or matrisome, an ensemble of 1000+ proteins, is a key interface between NGVU cells, interacting with endothelial cells, mural cells and astrocytic end-feet. The ECM provides essential structure and functional stability to the NGVU, disruption of which will have profound effects on the functional integrity of the NGVU.

We are aiming to investigate NVGU and ECM dysfunction in SVD by utilising complementary in-vivo mouse models and iPSC patient derived models, alongside ‘omics’ and patient cohorts.

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