BACKGROUND:

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Alzheimer’s Disease (AD) is the most common form of dementia characterised by clinical features such as cognitive decline, mobility issues and loss of speech. One pathological hallmark of AD is the aggregation of a protein called Tau. Tau is a protein that aids stability of axons (long extensions from the cell body), and aggregation of this protein leads to synaptic dysfunction and inevitably cell death. P2X7 receptor is found on astrocytes and microglia, both of which are cells that support surrounding neurons and aid their survival. Previous work by Dr Paula Belton-Lobo, in the Noble Group, found that P2X7 receptor is increased in AD postmortem brains, compared to non-diseased controls. Interestingly, when P2X7 is inhibited, we see a decrease in aggregated tau. This indicates that P2X7 is important in the pathology of AD, and the inhibition of this receptor could be a potential therapeutic target.

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METHODOLOGY:

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In our laboratory, we use brain slices that we sustain in a nutrient media for up to four weeks. On the day we obtain the slices, we add a virus that contains mutated tau which aggregates due to the changes in the amino acid sequence. Whilst we keep these slices viable, they slowly develop aggregates tau, like what is seen in AD. This allows us to see the impact of tau aggregation, in real time, in a brain environment.

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RESULTS:

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Previous work by Dr Paula Belton-Lobo, has been analysed and showed that inhibition of P2X7 resulted in a reduction of aggregated tau. We assess this by extracting the tau from four week old brain slices and centrifuging the sample at various speeds in the presence of 1% Sarkosyl. We obtain a low speed fraction (total tau), a high speed fraction (soluble tau) and a sarkosyl insoluble fraction (aggregated tau). These can be separated via electrophoresis through a gel. The image below shows wild-type human tau that does not aggregate and mutant human tau which does. The slices were treated for two weeks with C033, an inhibitor of P2X7 receptor, or DMSO as a control. We see a distinct reduction in aggregated tau in the mutant human tau slices treated with C033.

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FUTURE WORK: 

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I have designed some adeno-associated viruses (AAVs) which can inhibit the production of P2X7 in specifically microglia or astrocytes. This will allow us to decipher which cell type is more important in the pathology of AD as they both have different distinct molecular pathways that P2X7 regulates. Interestingly, cholesterol metabolism is dysregulated in astrocytes – and P2X7 has been implicated in this process, so it would be interesting to see if lipid metabolism is involved in AD.

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FUNDED BY:

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I would like to give a huge thank you to Alzheimer’s Research UK for funding this project, along with my supervisor Professor Wendy Noble for her continuous support, and the University of Exeter for allowing this research to be conducted.

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CONTACT: 

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