P2X7 Receptor: an apoE modulator and potential target in Alzheimer’s disease
University of British Columbia
Alzheimer’s Disease (AD) is the most common type of memory loss in the elderly. Apolipoprotein E (apoE) is a type of fat carrier in the brain and genetic changes in apoE greatly affect AD risk. In collaboration with AstraZeneca, we have identified small molecules that increase apoE production by human brain cells by inhibiting the P2X7 protein, which forms pores in cell membranes. Here we propose to test similar molecules so that we can improve drug activity and selectivity and understand more about how these molecules enhance apoE production. We will also study how the compounds work, by confirming that P2X7 is the cellular target that the compounds initially act on, evaluating the presence of P2X7 in AD models and performing experiments in a test tube to characterize how increasing apoE provides beneficial functions in halting AD.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
In Canada, a new case of AD is diagnosed every 7 minutes, making dementia one of the most pressing health challenges to face our generation. Currently none of the approved drugs address the disease and, at best, only offer a year or two of reduced symptoms. There is therefore a great need to develop effective AD targeted drugs and identify new relevant drug targets. ApoE has an undeniable role in the AD disease process and our ultimate goal centers on overcoming the detrimental effect specifically of the APOE4 gene that has the strongest genetic impact of increasing AD risk.
At the end of this funding period, we will validate P2X7 as a new target that controls apoE production and will identify compounds that are suitable for future testing in AD mouse models. This will represent great progress on the road to developing an effective AD drug.
Our project has sought to evaluate new small molecules that can increase apolipoprotein E (apoE) and ATP binding cassette transporter 1 (ABCA1) in human brain cells. ApoE is a fat carrier in the brain and impacts risk of Alzheimer’s disease. ABCA1 transfers fats onto apoE for transport, and boosting ABCA1 helps apoE function normally and can reverse some of the features of Alzheimer’s disease in experimental models. A subset of our small molecules were able to consistently increase ABCA1 levels and function and increase production of apoE though a mechanism that differs from previous drugs called ‘direct LXR agonists’ that have been used to boost ABCA1 and apoE but also cause undesirable side effects. Importantly, our test compounds do not appear to have this safety limitation.
The small molecules were originally developed as drugs to block a receptor protein called P2X7. As P2X7 can promote inflammation and may be involved in loss of functional brain cells as occurs in Alzheimer’s disease, blocking P2X7 is expected to have beneficial effects for Alzheimer’s disease. Intriguingly, by evaluating cells with no P2X7, we showed that the effect of the small molecules on ABCA1 and apoE occurs independently of P2X7 function. Hence these small molecules have two functions, one to block P2X7 and another to activate ABCA1 and apoE through a mechanism that remains to be defined. Our work has identified and validated small molecules that show ABCA1 and apoE activity in several different types of brain cells, and which also block P2X7. These compounds therefore have the ability to increase fat transport and reduce inflammation, both of which are very desirable features for potential Alzheimer’s disease therapeutics.