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Rosemary has a historical connection to memory; as noted by Ophelia in Shakespeare’s Hamlet, “There’s rosemary, that’s for remembrance.” With this legacy in mind, researchers have focused on a compound found in rosemary and sage known as carnosic acid, particularly for its potential effects on Alzheimer’s disease. This condition is the most prevalent cause of dementia and ranks as the sixth leading cause of death in the United States, where inflammation plays a significant role in cognitive decline associated with the disease.
Carnosic acid is recognized for its antioxidant and anti-inflammatory properties, functioning by stimulating enzymes that enhance the body’s inherent defense mechanisms. However, due to its instability, pure carnosic acid is not suitable for medicinal use. To address this limitation, scientists at Scripps Research have developed a stable variant called diAcCA. This new compound is metabolized into carnosic acid within the digestive system prior to entering the bloodstream.
The findings, which appeared in the journal Antioxidants on February 28, 2025, indicate promising results from treating mouse models of Alzheimer’s with diAcCA. The treatment achieved significant concentrations of carnosic acid in the brain, resulting in improved memory performance and increased synaptic density—an indicator of nerve cell connections. This synaptic preservation is essential since the loss of neuronal synapses is closely linked to dementia progression in Alzheimer’s.
Investigations of brain tissue revealed a noticeable reduction in inflammation following the treatment. The unique mechanism of diAcCA activates in response to the inflammation it targets, providing therapeutic action specifically within damaged areas of the brain. This careful targeting diminishes the risk of side effects associated with carnosic acid, which is already recognized as “generally regarded as safe” (GRAS) by the US Food and Drug Administration, facilitating its journey toward clinical evaluation.
Senior author and professor Stuart Lipton, MD, PhD, who holds the Step Family Foundation Endowed Chair at Scripps Research, commented, “By targeting inflammation and oxidative stress through diAcCA, we effectively increased the number of synapses in the brain.” He noted that the compound also helps reduce misfolded proteins, such as phosphorylated-tau and amyloid-β, which are considered pivotal in the onset of Alzheimer’s and serve as key biomarkers for the disease.
Previously, Lipton’s research had confirmed that carnosic acid could cross the blood-brain barrier and stimulate the Nrf2 pathway, which activates the body’s antioxidant and anti-inflammatory defenses. However, due to its easy oxidation, using carnosic acid directly as a medication posed challenges related to its stability.
In the recent study, Lipton and co-author Phil Baran, PhD, who holds the Dr. Richard A. Lerner Endowed Chair in the Department of Chemistry at Scripps Research, synthesized a variety of derivatives of carnosic acid, ultimately selecting diAcCA for its favorable properties, including its stability and bioavailability. They administered diAcCA to mouse models over a three-month period, assessing their spatial learning and memory via behavioral tests and conducting microscopic analyses of their brain tissues.
“We conducted various memory tests, and each indicated improvement with the drug,” Lipton remarked. “It didn’t merely halt the decline; it restored functionality to nearly normal levels.” The analysis of brain tissue demonstrated increased synaptic density and a decrease in the formation of toxic aggregates of phosphorylated-tau and amyloid-β.
The mice exhibited good tolerance to diAcCA. In toxicity assessments, the compound also appeared to alleviate baseline inflammatory conditions in the esophagus and stomach during its conversion to carnosic acid.
Additionally, the researchers observed that mice ingested about 20% more carnosic acid when using diAcCA compared to taking carnosic acid directly. Given that significant amounts of carnosic acid degrade during storage or digestion, “diAcCA results in higher blood levels of carnosic acid compared to taking it in its unmodified form,” Lipton clarified.
Lipton anticipates that diAcCA could complement existing Alzheimer’s therapies. It could act independently to manage inflammation and potentially enhance the efficacy of current amyloid antibody treatments while mitigating side effects such as ARIA-E and ARIA-H, conditions involving brain swelling or bleeding.
Given its favorable safety profile, Lipton is optimistic about the prospects for expediting diAcCA through clinical trials. He also envisions its application extending to other inflammation-related conditions, including type 2 diabetes, cardiovascular diseases, and different forms of neurodegeneration such as Parkinson’s disease.
This work was supported by funding from the National Institutes of Health (U01 AG088679, R01 AG056259, R35 AG071734, RF1 AG057409, R01 AG056259, R56 AG065372, R01 DA048882, DP1 DA041722 and S10 OD030332).
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