New drug targets for dementia

12 December 2018

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New technologies and advances in biology may impact the way we study and treat neurodegenerative disease…

According to Alzheimer’s Society, 850,000 people live with dementia in the UK, a number set to increase as the population ages. There is currently no cure for dementia, and development of new therapies is slowed by lack of understanding of the cell death and inflammation which characterises this family of diseases.

Combining studies in mice and human brain samples with multiple large-scale datasets, Vivek Swarup and his colleagues from the University of California Los Angeles identified two genetic networks which are off kilter in dementia. In genetic networks, the levels of various regulator signals interact to control the levels of a range of proteins that perform important roles in the cell. The new study, published in Nature Medicine, reveals how these networks may be targeted with drugs to limit the extent of neurological damage and potentially retard the progression of dementia.

One of the networks identified by Swarup and his team affects the connections between nerve cells, which are called synapses. The other network is associated with inflammation, and its activity is upregulated in dementia. This may be owing to overactivity of some of the classes of supporting cells found alongside nerve cells in the brain. It was by combining data from both patients and mice with the rodent form of dementia, the team uncovered patterns of gene expression identical in both the mice to humans.

The UCLA team also identified a molecule which acts as a global regulator for the synaptic network. It is part of a class of regulators called miRNAs, small molecules which can act at various stages in gene expression to control protein levels and shape cellular function. Inhibition of this regulator reversed disease-associated changes in the network activity. As various molecular approaches are becoming available to therapeutically target miRNAs, this may represent a fruitful approach in the future.

Encouragingly, at least two new drugs are predicted to reverse gene expression changes associated with deregulation of the synaptic and inflammatory networks. While they do not reverse the toxic protein accumulation associated with dementia, they could prevent downstream neuronal cell death, inflammation and their behavioural outcomes.

These advances were made possible by large databases for cell-type specific gene expression, predicted gene function, protein-protein interactions, population wide gene-disease associations, and libraries of drugs and their effects. Extensive use of databases to understand the networks that govern cellular function shows the power of big data, and how it will likely shape the biology and medicine of tomorrow.

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