For this week I had decided to read and summarise a paper published in J Neuroscience, about the protective role of aspirin in Alzherimer’s Disease (AD). I saw a link highlighting this paper on Facebook and could not immediately get access to the full text (paywalls). I did not even read the full title, but I already had 1 question: “did they check by correlation studies if there’s less people chronically taking aspirin, among those with AD? When I finally saw the full title of the paper, I realised that the study was more precise: “Aspirin induces Lysosomal biogenesis and attenuates Amyloid plaque pathology in a mouse model of Alzheimer’s disease via PPARα”.
Here I got a bit doubtful if I should still read the paper for this blog. But I persisted. My main concern being: why this particular pathway? The answer, which gets obvious mid-paper is: the authors seem to have worked on this one molecule before. But the rational to have chosen Aspirin as treatment seems to have a logical argumentation.
Stepping back: Alzheimer’s disease is caused by accumulation of Amyloid-beta (Abeta). This is a protein that can aggregate with others of the same type in such unbreakable structures that the aggregates are known as plaques. In general, protein aggregates would normally be broken down by the cell machinery: e.g. proteasome and lysosomes, but in AD it seems that this machinery is not working, or is not efficient enough. The authors point out that aspirin has been shown to increase the production of lysosomes.
For this study, the authors follow up on this increase of production of lysosomes by aspirin.
They started by adding Abeta to cells and then aspirin and check that indeed, cells treated with aspirin have less Abeta because 1) they take in less Abeta from the solution and 2) they get rid of the previously taken in Abeta, faster. To check the cause of this clearance, the authors checked for lysosome numbers and saw that it was increased in cells treated with aspirin. Moreover, they hypothesised this was due to new production of lysosomes and therefore looked into known transcription factors (TF) that promote lysosome biosynthesis. Having identified TFEB, they looked for enhancers of this TF and this was when they identified the PPRE site, and went on to study PPARs (Peroxisome proliferator-activated receptor), the pathway they have been familiar with. The next step in this paper is to distinguish between PPAR alpha, beta and gamma, by coupling Abeta-incubation with aspirin treatment in the presence and absence of inhibitors of these 3 molecules: meaning that the authors were able to see that when PPAR alpha was blocked, then aspirin treatment did not lead to increase lysosome production and Abeta was not broken down efficiently.
Pathway-studies done in cells is very useful to pin-point all the players in a certain process but it is not always a good model of the real situation. Therefore, the authors have used a mouse model of AD to test aspirin treatment in vivo: mice with 5 mutations in the Abeta production pathway, that are known to cause familiar AD in humans. These mice develop AD “spontaneously” after a certain age. Thus, once the mice had developed AD, the authors have treated these mice with aspirin, as well as a new set of mice that have the 5 mutations associated with AD and are deficient for PPARalpha. The conclusion is that in the group of mice that are deficient for PPARalpha, the accumulation of Abeta plaques is higher, because the same aspirin treatment is not effective anymore.
So, my question remains: is there a correlation in humans between those taking aspirin and decrease risk of Alzheimer’s disease? This study does not address that.
What this study points at is to a link between PPAR alpha mediated increased lysosome production after treatment with aspirin.
Notes & References
Transcription Factor (TF) – protein capable to bind to a sequence of DNA and therefore regulate gene expression.
Enhancer region – sequence of DNA to which TF bind.