Urolithin A protects against Alzheimer’s by blocking DYRK1A

The scientific paper by Tu et al., titled Urolithin A exhibits a neuroprotective effect against Alzheimer’s disease by inhibiting DYRK1A activity, explores a promising natural approach to addressing Alzheimer's disease (AD), a neurodegenerative disorder marked by memory loss and cognitive decline. Despite ongoing research, effective treatments that halt or reverse AD progression remain elusive. In this study, the authors investigated Urolithin A (UA), a gut microbiota-derived metabolite of ellagitannins, for its potential to target DYRK1A—an enzyme found at elevated levels in AD patients and known to contribute to tau protein hyperphosphorylation. Building on previous evidence of UA's antioxidant and anti-inflammatory effects, the researchers aimed to clarify its molecular mechanism and evaluate its therapeutic impact on both cellular and animal models of Alzheimer’s disease.

Alzheimer’s disease (AD) is a brain condition that slowly affects memory, learning, and thinking. It is the most common type of dementia and makes daily life hard for millions of people around the world. Right now, over 50 million people are living with this disease, and that number keeps growing.

Most current drugs for Alzheimer’s can only help with symptoms like memory loss. They do not stop or slow the disease. One of the reasons Alzheimer’s is so hard to treat is because the damage starts in the brain many years before symptoms show up. By the time people notice memory problems, their brain cells may already be harmed.

Two main signs of Alzheimer’s are:

• Amyloid-beta (Aβ : A sticky protein that forms plaques outside brain cells.
• Tau tangles: Twisted fibers inside cells made from a protein called tau, which becomes harmful when it’s too phosphorylated (when too many phosphate groups stick to it).

A special enzyme called DYRK1A (Dual-specificity tyrosine-phosphorylation-regulated kinase 1A) plays a big role in this process. People with Alzheimer’s have more DYRK1A in their brains than healthy people. This enzyme adds phosphates to tau protein, which makes tau clump together and form tangles.

This study focuses on a natural compound called Urolithin A (UA). UA is made in our bodies when gut bacteria break down ellagitannins, a type of antioxidant found in foods like pomegranates and walnuts. Earlier research showed UA might protect brain cells, but scientists weren’t sure how. This new study tries to answer that question.

The researchers used many scientific methods to test how UA affects Alzheimer’s-related changes in the brain:

• Kinase Profiling: UA was tested against 40 different protein kinases (enzymes) to see which ones it blocks. This helped the scientists identify its main target.
• Molecular Docking: Using 3D computer models, they looked at how UA fits into the DYRK1A enzyme’s active site.
• Cell Experiments: The team used human (HEK293, COS-7) and mouse (BV-2) cells. Some cells were made to overproduce DYRK1A and tau so researchers could see how UA affects tau phosphorylation and inflammation.
• Tubulin Polymerization Assay: This test showed if UA could help stabilize microtubules, which are essential structures in brain cells.
• Mouse Study: Mice were given okadaic acid, a chemical that causes brain damage similar to Alzheimer’s. Then, some mice were treated with UA to see if it helped them perform better in memory tests.
• Memory Test: The Morris water maze test was used to check if the mice remembered where to find a hidden platform in a pool.

Every step was done carefully and repeated to make sure the results were accurate. Differences between treated and untreated groups were checked using statistical analysis.

Out of the 40 kinases tested, UA worked best against DYRK1A. At a concentration of 3 micromolar (μM), UA reduced DYRK1A’s activity by 75%, more than any other enzyme. This was the first clear sign that UA might be acting as a DYRK1A inhibitor.

As the study says:

“DYRK1A is the main target of UA… [and] UA dose-dependently inhibited the activity of DYRK1A, with a half maximal inhibitory concentration (IC50) of 909 nM.”

This means the more UA was added, the stronger it blocked DYRK1A. It also suggests that UA competes with ATP, a molecule needed for kinase activity. So, UA likely works as an ATP-competitive inhibitor.

The scientists looked at how DYRK1A affects tau protein. When DYRK1A was overactive in the lab-grown cells, tau became heavily phosphorylated at key sites—Thr181, Thr212, Thr217, and Ser199/202—which are known to be involved in Alzheimer’s.

However, when cells were treated with UA, phosphorylation at all of these sites dropped.

“Treatment with UA reduced the phosphorylation… in a concentration-dependent manner,” the study confirms.

This suggests that UA not only blocks DYRK1A but also prevents the tau protein from becoming toxic.

Tau normally helps brain cells stay healthy by keeping microtubules stable. These are like tiny highways inside the cells that carry nutrients and signals. When tau is too phosphorylated, it can't do this job anymore, and the microtubules break apart.

The study showed that UA helped fix this problem. In a special cell-free system, UA helped keep microtubules from falling apart, even when DYRK1A and tau were both present.

The researchers wrote:

“Inhibition of DYRK1A by adding UA dose-dependently stabilized tubulin and increased turbidity.”

More turbidity (cloudiness in the solution) meant more stable microtubules.

The team also studied inflammation. They used BV-2 microglial cells, similar to immune cells in the brain. These cells were exposed to oligomeric amyloid-beta (oAβ)—a toxic form of amyloid protein.

This caused:

• Cell death.
• An increase in inflammatory signals, especially IL-6 and TNF-α.

But the harmful effects were reversed when the cells were pretreated with UA.

“Pretreatment with UA successfully reversed expressions of these inflammatory cytokines,” the study notes.

This means UA might help reduce brain inflammation, which is often a big problem in Alzheimer’s.

The study's final and most exciting part was testing UA in mice. The mice were given okadaic acid, which causes tau phosphorylation and memory problems, similar to Alzheimer’s. Some mice were treated with daily UA injections (100 mg/kg).

The results:

• Mice treated with UA found the hidden platform faster.
• They traveled shorter distances.
• Their memory of the correct area improved.

As the study says:

“Treatment with UA reversed this memory defect… and reduced phosphorylation of Tau at Thr-212 in hippocampal tissue.”

This shows that UA’s benefits in cells also happen in living animals, making it a strong candidate for further testing.

This scientific paper shows that Urolithin A could help protect the brain in many ways:

• It blocks DYRK1A, an enzyme that worsens tau-related brain damage.
• It stops tau protein from becoming over-phosphorylated and harmful.
• It stabilizes brain cell structures called microtubules.
• It lowers inflammation and protects cells from dying.
• It improves memory in mice with Alzheimer’s-like symptoms.

Because UA comes from natural sources like pomegranates and is already made in the human body, it may be a safe option to explore as a daily supplement for brain health. The fact that UA can cross the blood-brain barrier makes it even more promising.

However, scientists stress that more research is needed, especially in human trials, to see if these results apply to people.

The study offers strong evidence that Urolithin A has neuroprotective powers. By targeting the enzyme DYRK1A, UA blocks one of the key steps in Alzheimer’s progression—tau phosphorylation. It also calms inflammation, protects neurons, and improves memory in animal models.

Because UA is safe, natural, and already present in the body, it has enormous potential to be developed as a supplement for brain health or early Alzheimer’s prevention. If future studies confirm these results in humans, UA could become a simple but powerful way to help fight Alzheimer’s disease naturally.