Different versions of RNA encoded by single genes may play a role in Alzheimer’s disease, according to a new study published in the journal ‘Science Advances’. The researchers analyzed brain tissue from deceased organ donors and found 700 RNA isoforms that had never been described before. And they found that the levels of nearly 100 of these isoforms differed in the brains of people with and without Alzheimer’s. Notably, the genes behind these isoforms were equally active in both groups of people. This suggests that if scientists only look at a gene’s overall activity but not at the different RNAs it’s making, they miss out on this nuance.
The researchers used a technique called ‘long-read sequencing’ to take a snapshot of RNA present in the brain tissue. Of the 700 newfound isoforms, 430 could be connected back to known genes, and of those, 53 came from genes that had been tied to health conditions in previous studies. Notably, two genes related to the abnormal amyloid and tau proteins seen in Alzheimer’s — APP and MAPT — respectively gave rise to five and four isoforms.
A few isoforms stood out when the team compared the brains of the Alzheimer’s patients to those without the disease. For example, a gene called TNFSF12 made two distinct isoforms, the first of which was boosted in the brains of people with Alzheimer’s and the second of which was higher in healthy brains. In the past, the TNFSF12 gene has been tied to the inflammatory response in the brain, but because the gene makes multiple isoforms, more work may be needed to reveal which one is actually behind this inflammation.
However, because the recent study included only 12 brains, it’s too soon to know if these results carry over to others with and without Alzheimer’s, the researchers stressed. To expand their data set and see which results do carry over, co-first author Dr. Jessica Heberle, a research assistant professor at the University of Kentucky College of Medicine, is now leading an effort to conduct the same study with more than 300 brains.
In the long run, the researchers hope certain RNA isoforms may be prime targets for future Alzheimer’s drugs.
