Postgraduate research opportunities Is PAR2 activation neuroprotective in a mouse model of Alzheimer’s Disease?

Dementia is the only one of the top ten causes of death in the UK that has no treatment that can either cure or slow its progress¹, with current treatments primarily offering symptomatic relief rather than targeting the disease itself. Our understanding of AD aetiology is an area of intense research² but drug development has proved difficult. Hence there is a clear need for novel therapeutic strategies and targets and we propose that one such target is proteinase-activated receptor 2 (PAR2). There is strong evidence that PAR2 plays a protective role in in vitro neurotoxicity assays and in certain CNS disorders³.  Recently novel non-peptidic PAR2 activators with high potency and good stability have been developed and our recent work has revealed that one of these novel agonists, AC264613⁴, is a good candidate with which to examine the therapeutic potential of PAR2 in CNS disorders as we have shown that it mimics the neuroprotective properties of classical PAR2 activators in in vitro excitotoxicity assays, crosses the blood brain barrier (BBB) and results in immunomodulation similar to that observed in AD resilient patients⁵.

In this project, we aim to capitalise on our recent novel observations by testing the hypothesis that AC-264613 is protective in a mouse model of AD. Thus the aim of this project is to test this hypothesis using the 5xFAD mouse model of AD⁶ to examine the following research questions:

1. Does PAR2 activation reduce β-amyloid load observed in 5xFAD mice?
2. What cellular and signalling pathway(s) underlie PAR2-induced neuroprotection?
3. Does immunomodulation plays a key role in PAR2-induced neuroprotection??

Answer to these questions will identify a potential novel therapeutic target for the treatment of AD.

Techniques used

Behavioural testing of 5xFAD mice, immunohistochemistry, innate and adaptive immune cell assays using FACS analysis, cytokine assays using ELISA and qPCR.