The “amyloid hypothesis,” the widely accepted theory that Alzheimer’s is brought on by a buildup of beta-amyloid proteins in the brain, has new support thanks to an analysis of human brain cells.
In the study, scientists from Columbia University discovered that amyloid causes an alliance between two proteins in the brain’s neurons and that this pairing is connected to roughly half of the gene changes known to occur in the disease, causing the rapid accumulation of tau proteins, a key factor in the disease’s neurodegeneration.
Ulrich Hengst, Ph.D., the study’s senior author, notes that “this protein pair seems to be very central to the disease, and because it does not appear to have another function in the brain, it is a good target for a new therapy.” D. is an associate professor of pathology and cell biology at the Columbia University Vagelos College of Physicians and Surgeons’ Taub Institute for Research on Alzheimer’s Disease and the Aging Brain.
“This protein pair appears to be very fundamental to the condition, and because it does not appear to have another role in the brain, it is an excellent target for a new therapy,”
Ulrich Hengst, Ph.D., associate professor of pathology & cell biology.
The protein pair was a secret in earlier studies.
The two were discovered by the researchers as they searched for proteins that trigger the hundreds of changes in gene activity that take place in brain cells during Alzheimer’s disease. Claudio Gouveia Roque, Ph.D., explains, “Our theory was that if we could interfere with the proteins and prevent those changes, we could prevent the disease.”. D., the study’s principal investigator and associate research scientist in the Hengst lab.
The researchers searched for pairs of various proteins cooperating together rather than proteins that act alone.
Although we are aware that this kind of protein must always work in pairs, previous studies on Alzheimer’s disease hadn’t specifically looked for these pairs. As a result, Hengst claims, “our knowledge of the changes underlying the progression of Alzheimer’s disease has been fragmented and lacking. And as a result, we have probably passed up therapeutic opportunities.”.
Proteins clump together due to amyloid.
The research by Hengst and Gouveia Roque, along with a former associate research scientist in the Hengst lab, Jimena Baleriola, identified two proteins—ATF4 and CREB3L2—whose binding to one another is triggered by amyloid and which together interact with about 50% of the gene expression changes that take place in brain cells during Alzheimer’s disease.
Once established, the CREB3L2-ATF4 pair activates a network of other proteins that lead to the buildup of lethal tau deposits inside neurons. Another characteristic of Alzheimer’s disease is the protein pair’s ability to shut down the cellular machinery that removes faulty proteins from neurons.
Although CREB3L2 and ATF4 are also present separately in healthy neurons, the researchers discovered that the strength of their binding increases significantly in the presence of a stress like an excess of amyloid.
Hengst claims that “these two proteins are like two teenage boys.”. Individually, they might be relatively safe. But if you mix them up without a responsible adult present, they might get into mischief.”.
New method of therapy.
According to the research, blocking the CREB3L2-ATF4 pair could be used to treat Alzheimer’s.
Because they regulate too many genes, proteins that control gene activity typically make terrible drug targets. However, by focusing on this pair, we may be able to maintain the functionality of the two proteins while avoiding the negative effects of their binding together, according to Hengst.
Dovitinib is a medication that Hengst and Gouveia Roque have already discovered blocks the actions of the protein pair. The FDA has given dovitinib the go-ahead to treat renal cancer, but tests on the drug’s ability to treat Alzheimer’s disease have not been conducted. Although the drug crosses the blood-brain barrier, Hengst notes that it is not toxic to neurons, which is encouraging for the development of new drugs.
With this method, Gouveia Roque continues, “We’re not talking about getting rid of amyloid.”. “If we can disrupt the protein pair, we might be able to stop the disease’s progression entirely. Although there would still be some amyloid in the brain, the neurons would respond to it much less. It is conceivable that such a medication could be combined with one that lowers amyloid levels to achieve even greater results.
The article appears in the journal Science Advances.
More information: Cláudio Gouveia Roque et al, CREB3L2-ATF4 heterodimerization defines a transcriptional hub of Alzheimer’s disease gene expression linked to neuropathology, Science Advances (2023). DOI: 10.1126/sciadv.add2671
