Scientists have discovered that a modified form of a natural compound found in rosemary and sage may hold potential for treating Alzheimer’s disease. In a new study using mouse models of Alzheimer’s, this compound improved memory, boosted brain connections, and reduced harmful inflammation in the brain, suggesting a promising new approach to combatting this devastating illness. The research was published in the journal Antioxidants.
Alzheimer’s disease, a condition that robs people of their memories and thinking abilities, is a major health concern around the world. Researchers are constantly seeking new ways to prevent or treat this disease, which is characterized by several complex processes in the brain. One significant aspect of Alzheimer’s is inflammation. Brain inflammation is thought to contribute to the damage of brain cells and the cognitive decline seen in Alzheimer’s patients. Scientists are interested in finding ways to reduce this inflammation as a strategy to protect the brain and slow down the progression of the disease.
Inspired by the historical association of rosemary with memory, researchers turned their attention to carnosic acid, a compound naturally present in rosemary and sage. Carnosic acid is known for its antioxidant and anti-inflammatory properties, acting by activating the body’s own defense mechanisms. However, carnosic acid in its pure form is not stable enough to be used as a medication.
To overcome this hurdle, scientists at Scripps Research developed a stable version of carnosic acid, called diAcCA. This new form is designed to be easily absorbed by the body. Once ingested, diAcCA is converted into carnosic acid in the gut before entering the bloodstream. The researchers wanted to investigate if this stable form of carnosic acid could effectively treat Alzheimer’s-like symptoms in a laboratory setting.
To test their new compound, the research team used mice that were genetically engineered to develop features of Alzheimer’s disease. These mice, known as models of Alzheimer’s, develop problems with memory and brain changes similar to those seen in humans with the disease. The study involved 45 mice in total. Some of these mice were healthy, while others were the Alzheimer’s model mice.
The mice were divided into groups, with each group receiving a different treatment over three months. Some groups of Alzheimer’s mice received diAcCA at varying doses – 10 milligrams per kilogram of body weight, 20 milligrams per kilogram, or 50 milligrams per kilogram. Another group of Alzheimer’s mice and a group of healthy mice received a placebo, which was just olive oil. The treatments were given orally, three times a week. After the treatment period, the researchers conducted memory tests and examined the brains of the mice to see how the compound had affected them.
The researchers discovered that diAcCA successfully delivered therapeutic levels of carnosic acid to the brains of the mice. Importantly, the Alzheimer’s mice treated with diAcCA showed significant improvements in memory. In memory tests designed to assess spatial learning and recall, the treated mice performed much better than the untreated Alzheimer’s mice, almost returning to the level of healthy mice.
Further examination of the brain tissue revealed that diAcCA had a positive impact on the connections between brain cells, known as synapses. Synapses are essential for communication between nerve cells and are critical for learning and memory. The treated mice showed increased synaptic density, meaning they had more of these vital connections in their brains. This increase in synapses suggests that diAcCA was helping to repair or protect these crucial brain connections.
In addition to improvements in memory and synapses, the researchers found that diAcCA significantly reduced inflammation in the brains of the Alzheimer’s mice. Tissue analysis showed a marked decrease in inflammatory markers. A unique aspect of this drug is its targeted action. It is activated by inflammation itself, meaning it becomes more active in areas of the brain that are experiencing inflammatory damage. This selective activation could limit potential side effects, which is a significant advantage.
The researchers also observed a reduction in the hallmark proteins of Alzheimer’s disease: amyloid beta plaques and phosphorylated tau tangles. These abnormal protein clumps are thought to be major contributors to the disease process. DiAcCA treatment reduced the presence of both of these proteins in the mouse brains.
“By combating inflammation and oxidative stress with this diAcCA compound, we actually increased the number of synapses in the brain,” explained senior author and professor Stuart Lipton, the Step Family Foundation Endowed Chair at Scripps Research and a clinical neurologist in La Jolla, California. “We also took down other misfolded or aggregated proteins such as phosphorylated-tau and amyloid-β, which are thought to trigger Alzheimer’s disease and serve as biomarkers of the disease process.”
Interestingly, the mice tolerated diAcCA well, and toxicity studies even suggested that it might have a soothing effect on mild inflammation in the digestive system. Furthermore, the body absorbed carnosic acid more effectively when it was administered as diAcCA compared to pure carnosic acid, meaning diAcCA is a more efficient way to deliver the beneficial compound.
While these findings are promising, the researchers acknowledge some limitations. The study was conducted in mice, and results in animal models do not always perfectly translate to humans. Future research is needed to confirm these findings in human studies. However, because carnosic acid itself is considered safe for human consumption by the Food and Drug Administration, the path to clinical trials for diAcCA could be faster than for entirely new drugs.
Looking ahead, the researchers suggest that diAcCA could be explored not only as a standalone treatment for Alzheimer’s disease but also in combination with existing Alzheimer’s therapies. It is possible that diAcCA could enhance the effectiveness of current treatments and potentially reduce their side effects. Beyond Alzheimer’s, the scientists believe diAcCA’s anti-inflammatory properties could be beneficial in other conditions marked by inflammation, such as type 2 diabetes, heart disease, and other brain disorders like Parkinson’s disease. This research opens up an exciting avenue for developing new treatments for Alzheimer’s and potentially other related conditions, drawing upon the power of natural compounds found in everyday herbs.
The study, “diAcCA, a Pro-Drug for Carnosic Acid That Activates the Nrf2 Transcriptional Pathway, Shows Efficacy in the 5xFAD Transgenic Mouse Model of Alzheimer’s Disease,” was authored by Piu Banerjee, Yubo Wang, Lauren N. Carnevale, Parth Patel, Charlene K. Raspur, Nancy Tran, Xu Zhang, Ravi Natarajan, Amanda J. Roberts, Phil S. Baran, and Stuart A. Lipton.
