The Future of Alzheimer's Treatment: Natural Compound Derived from Rosemary Improves Memory and Fights Brain Inflammation
- Lidi Garcia
- Mar 17
- 5 min read
Alzheimer’s disease is a disease that affects memory and other brain functions, especially in older people. Scientists are studying a natural compound called carnosic acid, found in rosemary and sage, for its potential benefits for the brain. To make it more effective, they created an improved version called diAcCA, which can be taken as a medicine. In tests on mice, this compound helped improve memory and reduce inflammation in the brain, showing potential for future treatments in humans.
Alzheimer’s disease (AD) is a progressive and relentless neurodegenerative condition that primarily affects the brains of older people. It is the sixth leading cause of death in the United States and is also the most common form of dementia in older people.
The main characteristic of the disease is the accumulation of harmful substances in the brain, such as amyloid-β (Aβ) plaques and phosphorylated tau (pTau) tangles, which affect areas of the brain essential for memory, such as the hippocampus and cortex.
This buildup leads to damage to the connections between neurons, known as synaptic damage, which causes a gradual decline in cognitive functions, such as memory and learning. One of the causes of this damage is oxidative and nitrosative stress, which occurs when there is an imbalance between substances that cause oxidation (damage) and those that protect cells, which is enhanced by the Aβ peptide.
All cells in the body have a natural defense system against stress called redox balance. This balance between oxidation and reduction is essential for cellular health.
When this system becomes unbalanced, it can cause health problems, including neurodegenerative diseases such as Alzheimer's disease. Electrophiles, which are substances capable of altering this balance, can be both beneficial, activating the body's defenses, and harmful, causing damage to cells and even leading to cancer.
Carnosic acid (CA), found naturally in the herbs rosemary and sage, is a substance with antioxidant and anti-inflammatory properties that, under certain conditions, can act as an electrophile.
In tissues affected by oxidative stress, carnosic acid activates cellular defense pathways, stimulating the production of proteins that protect against inflammation and cellular damage.
One such pathway is Nrf2, which helps regulate the cells' antioxidant defense. When this pathway is disabled, as occurs in diseases such as Alzheimer's, cellular damage intensifies. Carnosic acid, by activating Nrf2, can help combat this damage and protect the brain.
Several studies have shown that carnosic acid treatment has a neuroprotective effect, especially in mouse models of Alzheimer's disease. In one study, carnosic acid was administered nasally to mice with Alzheimer's disease, and the results showed a significant reduction in amyloid plaques and tau tangles, as well as an improvement in learning and memory in these mice.
However, one limitation of carnosic acid is that it is highly unstable and can oxidize quickly, which makes it difficult to use as a drug effectively, especially orally.
To overcome this limitation, researchers at The Scripps Research Institute, USA, created more stable derivatives of carnosic acid, such as diacetylated (diAcCA), which has shown to be a promising option for the treatment of Alzheimer's disease.
DiAcCA has the advantage of being more stable and being converted to carnosic acid in the stomach, which facilitates its absorption and use by the body. This derivative showed better bioavailability, that is, it is more easily absorbed and used by the body, and has excellent pharmacokinetics, reaching therapeutic levels in the brain in less than an hour.
When administered orally, diAcCA did not cause toxic effects on the digestive system, which is a major advance, since many compounds can cause damage when ingested orally. To test the efficacy of diAcCA, researchers conducted a study with mice genetically modified to present Alzheimer's Disease (5xFAD model).
These mice were treated with diAcCA or a placebo for three months, and the results showed that diAcCA was able to rescue the loss of neurons and synapses in the brain.
diAcCA treatment restores deficits in neuronal and synaptic density in 5xFAD mice. Quantitative immunohistochemistry (Q-IHC) analysis was performed on hippocampal sections from 5xFAD mice and WT mice treated with diAcCA (10 mg/kg, 20 mg/kg, or 50 mg/kg) or olive oil (vehicle, Veh). (A) Representative images showing antibody staining against NeuN, a neuronal marker, in hippocampal sections from WT and 5xFAD mice. (B) Bar graph quantifying the mean fluorescence intensity (MFI) of NeuN. diAcCA treatment restored NeuN MFI (indicating neuron quantity) to near-normal levels in 5xFAD mice. (C) Representative images showing antibody staining against Synapsin I, a marker located at the presynaptic terminal of the synapse, in the WT and 5xFAD treatment groups. (D) Bar graph quantifying the MFI of Synapsin I. Treatment with diAcCA restored the MFI of Synapsin I to near-normal levels in 5xFAD mice.
In addition, the treatment reduced amyloid plaques and tau aggregates, and decreased inflammation in the brain, a major contributor to disease progression.
The treatment also improved the learning and memory of the mice in behavioral tests such as the Morris water maze, which assesses spatial memory, and the conditioned fear test, which assesses emotional memory.
The study also showed that diAcCA was well tolerated and safe, and toxicity data indicated that it was as safe as carnosic acid itself, which is already considered safe for consumption by the FDA (US Food and Drug Administration).
This suggests that diAcCA has the potential to be used in human clinical trials for the treatment of Alzheimer's disease.
In summary, diAcCA is a promising form of therapy for Alzheimer's disease, offering antioxidant and anti-inflammatory benefits, and with good stability and bioavailability for oral administration, which makes it a viable option for the treatment of Alzheimer's in the future.
READ MORE:
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
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
Antioxidants 2025, 14(3), 293
Abstract:
The antioxidant/anti-inflammatory compound carnosic acid (CA) is a phenolic diterpene found in the herbs rosemary and sage. Upon activation, CA manifests electrophilic properties to stimulate the Nrf2 transcriptional pathway via reaction with Keap1. However, purified CA is readily oxidized and thus highly unstable. To develop CA as an Alzheimer’s disease (AD) therapeutic, we synthesized pro-drug derivatives, among which the di-acetylated form (diAcCA) showed excellent drug-like properties. diAcCA converted to CA in the stomach prior to absorption into the bloodstream, and exhibited improved stability and bioavailability as well as comparable pharmacokinetics (PK) and efficacy to CA. To test the efficacy of diAcCA in AD transgenic mice, 5xFAD mice (or littermate controls) received the drug for 3 months, followed by behavioral and immunohistochemical studies. Notably, in addition to amyloid plaques and tau tangles, a hallmark of human AD is synapse loss, a major correlate to cognitive decline. The 5xFAD animals receiving diAcCA displayed synaptic rescue on immunohistochemical analysis accompanied by improved learning and memory in the water maze test. Treatment with diAcCA reduced astrocytic and microglial inflammation, amyloid plaque formation, and phospho-tau neuritic aggregates. In toxicity studies, diAcCA was as safe or safer than CA, which is listed by the FDA as “generally regarded as safe”, indicating diAcCA is suitable for human clinical trials in AD.
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