A plant-based compound derived from Rosmarinus officinalis (rosemary) and Salvia officinalis (sage) has been re-engineered into a drug that may reverse neurological damage associated with Alzheimer’s disease, researchers at Scripps Research report. The newly developed synthetic compound, called diAcCA, was shown to enhance memory function, reduce hallmark protein accumulations, and rebuild critical brain synapses in mouse models of Alzheimer’s.
These findings, recently published in Antioxidants, could pave the way for a safer and more targeted therapy for neurodegenerative diseases that are currently difficult to treat.
A natural antioxidant reimagined for drug development
Carnosic acid, a naturally occurring compound found in rosemary and sage, is well known for its antioxidant and anti-inflammatory activity. It operates by stimulating a cellular defense system that neutralizes oxidative stress—one of the drivers of neurodegenerative disorders like Alzheimer’s. However, carnosic acid is unstable in its raw form and degrades easily, limiting its therapeutic potential.
In response to this challenge, a team led by Dr. Stuart Lipton, MD, PhD, a professor and neurologist at Scripps Research, collaborated with Dr. Phil Baran, PhD, a noted chemist also at Scripps, to synthesize a more stable derivative. The result was diAcCA, a prodrug that is fully converted into active carnosic acid in the gut, ensuring greater absorption and a longer shelf-life.
Activation only where it’s needed
One of the novel features of diAcCA is its selective activation in inflamed regions of the brain. This unique property allows it to minimize side effects and concentrate its effects where they’re most needed.
“By combating inflammation and oxidative stress with this diAcCA compound, we actually increased the number of synapses in the brain,” said Dr. Stuart Lipton. Synaptic density—the number of connections between neurons—is critical for cognitive function and is often diminished in patients with Alzheimer’s.
Additionally, the compound significantly reduced levels of two signature Alzheimer’s proteins: amyloid-β and phosphorylated tau. These toxic aggregates interfere with neuronal function and are considered central biomarkers of the disease.
Behavioral and molecular improvements observed
In a three-month study, Lipton’s team administered diAcCA to mouse models genetically engineered to simulate Alzheimer’s disease. The mice were evaluated through behavioral assessments measuring spatial memory and learning capabilities, as well as through microscopic brain tissue analysis.
“We did multiple different tests of memory, and they were all improved with the drug,” Lipton said. “And it didn’t just slow down the decline; it improved virtually back to normal.”
The treatment restored synaptic connections and curtailed the buildup of toxic protein aggregates—two key hallmarks of neurodegeneration.
These results align with growing evidence that oxidative stress and inflammation are upstream drivers of neuronal loss in Alzheimer’s. Reducing these factors can allow the brain to restore structural and functional integrity, even after damage has occurred.
Higher bioavailability and gut benefits
Not only was diAcCA well tolerated, but it also provided better absorption than regular carnosic acid. Mice receiving the synthetic derivative absorbed about 20% more carnosic acid, likely because of improved bioavailability.
Interestingly, toxicity tests revealed additional benefits: diAcCA appeared to reduce low-level inflammation in the gastrointestinal tract, including the esophagus and stomach. This systemic anti-inflammatory effect suggests broader therapeutic potential.
You can read more about carnosic acid’s biological activity and its role in neuroprotection.
Toward clinical trials and combination therapies
Because carnosic acid is already listed on the U.S. Food and Drug Administration’s GRAS (Generally Recognized as Safe) list, diAcCA has a favorable safety profile that could help expedite clinical trials. Dr. Lipton emphasized that the compound may be particularly valuable as an adjunctive treatment.
He noted its potential synergy with amyloid-targeting antibodies currently approved for Alzheimer’s treatment. “It could make existing amyloid antibody treatments work better by taking away or limiting their side effects,” such as ARIA-E (amyloid-related imaging abnormalities with edema) and ARIA-H (hemorrhage), Lipton said.
Additionally, the inflammation-targeting mechanism of diAcCA means it could be applicable in treating other chronic inflammatory diseases, such as Parkinson’s disease, heart disease, and type 2 diabetes.
A step forward in natural compound therapeutics
While more testing in human subjects is needed, this study underscores the value of revisiting traditional plant-based compounds through the lens of modern chemistry and neuroscience. By engineering stability and specificity into carnosic acid, the researchers have transformed a promising—but previously impractical—molecule into a potential therapeutic with broad implications.
As Dr. Lipton puts it, the goal is to create not only a more effective Alzheimer’s treatment but one that aligns with the body’s own healing systems. “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,” he said.
If clinical trials confirm the safety and efficacy observed in animal models, diAcCA could represent a rare combination: a naturally derived, orally available, and brain-penetrant therapy for a condition that has long evaded effective treatment.
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