New research from Columbia University provides further evidence for the “amyloid hypothesis,” which states that the accumulation of beta-amyloid proteins in the brain is the primary cause of Alzheimer’s disease. The study found that amyloid triggers an alliance between two proteins in the brain’s neurons, leading to about half of the gene changes that occur in Alzheimer’s. The protein pair – ATF4 and CREB3L2 – then causes the rapid accumulation of tau proteins, which are a primary driver of neurodegeneration in the disease.
The researchers discovered the protein pair when they were looking for proteins that spark hundreds of changes in gene activity during Alzheimer’s. Previous Alzheimer’s research hadn’t looked for specific pairs, leading to an incomplete understanding of the changes underlying Alzheimer’s progression. The ATF4 and CREB3L2 pair is a good target for new therapy, as it doesn’t appear to have another function in the brain.
The CREB3L2-ATF4 pair activates a network of other proteins that cause deadly tau deposits to accumulate inside neurons. The protein pair also disables the cellular machinery that clears old and damaging proteins from neurons, another hallmark of Alzheimer’s. Although CREB3L2 and ATF4 are also found alone in healthy neurons, their binding together is greatly increased in the presence of excess amyloid.
Interfering with the CREB3L2-ATF4 pair may be a viable treatment approach for Alzheimer’s. The researchers have already identified a drug, dovitinib, that interferes with the effects of the protein pair. While the drug has been approved by the FDA for renal cancer treatment, it has not been tested for Alzheimer’s. However, the drug is not toxic to neurons and crosses the blood-brain barrier, making it a promising candidate for future drug development. Targeting this pair might help preserve the function of the individual proteins while preventing the bad effects of them binding together. Although amyloid would still be present in the brain, a drug that interferes with the protein pair could slow or even stop the progression of Alzheimer’s.
The study suggests a new approach to treat Alzheimer’s disease by interfering with the pairing of two proteins in the brain’s neurons, called CREB3L2 and ATF4. These proteins are triggered by amyloid and cause half of the gene changes that are known to occur in Alzheimer’s, leading to the rapid accumulation of tau proteins, which are a primary driver of neurodegeneration in the disease. The study’s senior author, Ulrich Hengst, suggests that the protein pair is a good target for a new therapy since it does not appear to have another function in the brain.
Normally, proteins that control gene activity are not suitable drug targets as they control too many genes. However, targeting this pair might preserve the function of the two individual proteins while preventing the bad effects of them binding together. Hengst and Cláudio Gouveia Roque have already identified a drug called dovitinib, which interferes with the effects of the protein pair. Although the drug has been approved by the FDA for the treatment of renal cancer, it has not been tested for Alzheimer’s. Nonetheless, the drug is not toxic to neurons and crosses the blood-brain barrier, which bodes well for future drug development, according to Hengst.
The new approach is not about getting rid of amyloid; instead, it is about interfering with the protein pair to slow or stop the progression of the disease. Amyloid would still be present in the brain, but the neurons would react far less to it. Combining this drug with an amyloid-reducing drug could also have an even greater effect. The paper describing the findings is published in the journal Science Advances.