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Case study

The role of P2Y6R in mice in cognition, neuronal loss and tauopathy

Lead PI: Prof Guy Brown, University of Cambridge

Pharmacological inhibition of P2Y6 prevents neuronal loss induced by inflammatory stimuli, such as amyloid beta, in culture and in vivo. There is evidence that suggests P2Y6 plays a critical role in UDP-dependent phagocytosis of neurons. Thus, blocking P2Y6 would be expected to prevent neuronal loss and possibly synaptic loss in AD, and therefore prevent or delay long-term cognitive decline in patients. The project aimed to validate, develop and perform high throughput screens to identify P2Y6 receptor antagonists as potential therapeutic agents for Alzheimer's disease.

Prof Guy Brown

University of Cambridge, UK

"The Dementia Consortium project provided…invaluable expertise and advice in translation and drug development…[the] hands-on expertise of the Dementia Consortium team was invaluable."

Outcomes

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Validated P2Y6R as a novel dementia drug target, relevant to human disease with a critical role in excessive neuronal phagocytosis during neurodegeneration

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P2Y6R knockout in pre-clinical tauopathy models prevented cortical neuronal loss, tau pathology and memory deficits

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Assay suitable for high-throughput screening of P2Y6R antagonists was developed, optimised and validated

Future work

Industry

Professor Brown has now partnered with Sosei Heptares who have an interest in G-protein coupled Receptor (GPCR) medicines development for further drug development based on research funded by the Dementia Consortium.

 

Academia

A collaboration between the Drug Discovery Alliance (ARUK-funded) and Prof Brown has led to a joint grant application to the MRC for further validation and drug development on P2Y6, based on the research funded by the Dementia Consortium.