Urolithin A Improves Alzheimer's Cognition and Restores Mitophagy

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by memory loss, cognitive decline, and the buildup of toxic proteins such as amyloid-beta and tau. Disruptions in cellular waste-clearing systems, especially mitophagy (the removal of damaged mitochondria) and lysosomal function, play a key role in the disease's progression. In the scientific paper Urolithin A improves Alzheimer’s disease cognition and restores mitophagy and lysosomal functions, Hou et al. explore the therapeutic potential of Urolithin A (UA)—a natural compound produced by gut microbes from foods like pomegranates—in treating Alzheimer’s. Building on prior research showing UA’s ability to promote mitochondrial health, this study investigates its long-term effects in mouse models of AD, revealing promising improvements in memory, brain inflammation, and cellular repair systems.

Alzheimer’s disease (AD) affects millions of people around the world, and its rates are expected to triple by 2050. People with AD experience memory loss, difficulty thinking, and changes in behavior. The disease is linked to toxic proteins in the brain, especially amyloid-beta (Aβ) and tau, which damage neurons and lead to cell death.

Another problem in AD is that brain cells can't clean up waste properly. This happens because of poor autophagy, the process where cells break down and remove damaged parts. Mitophagy is a key part of this system, which clears out broken mitochondria—the cell’s powerhouses. When mitophagy doesn’t work, damaged mitochondria build up and hurt the brain.

Urolithin A (UA) is a natural substance made in our gut after eating foods like pomegranates and berries. It’s known to boost mitophagy and help cells stay healthy. In earlier studies, UA improved memory in mice with AD when given for a short time. This new study looked at what happens when UA is given long-term, and how exactly it helps the brain.

“Our study highlights the importance of lysosomal dysfunction in AD etiology and points to the high translational potential of UA.”

The scientists used three types of genetically modified mice that develop Alzheimer’s-like symptoms:

• APP/PS1 mice: used to study amyloid buildup
• 3xTgAD mice: used to study both amyloid and tau buildup
• 3xTgAD/Polβ+/− (ADP) mice: a model that also has problems with DNA repair, like in human AD

These mice were treated with Urolithin A for 5 months by oral gavage (a feeding method with a tube). They started treatment either before or after symptoms appeared.

To see how UA worked, researchers did:

• Behavioral tests (like the Morris water maze and Y-maze)
• Brain tissue studies (using ELISA, qPCR, Western blot, immunostaining)
• Electrophysiology to test brain cell communication
• Gene expression analysis with microarrays and NanoString technology

All tests were done under careful controls, with random assignment and blinded data analysis.

The mice that got Urolithin A showed considerable improvements in memory and learning. In the Morris water maze test, treated mice found the hidden platform faster than untreated ones, showing better learning.

In the Y-maze test, treated mice explored new paths more often—another sign of stronger memory. The mice kept some of their memory improvements even one month after stopping UA.

“Long-term UA treatment significantly improves learning and memory, olfactory function, and synaptic function of neurons.”

In the brain, neurons talk to each other using signals. One important signal is called long-term potentiation (LTP). The study restored LTP in UA-treated mice, showing that brain connections worked better.

The study showed that UA reduced amyloid-beta plaques, especially in the prefrontal cortex, a brain area tied to thinking and decision-making. It also lowered tau phosphorylation at key sites like Thr181 and Thr231, which are linked to brain damage in AD.

The study found that UA helped fix lysosomal function —the system that breaks down and removes waste in cells. UA increased the breakdown of proteins and helped keep the right acid levels in lysosomes.

A key finding was the role of cathepsin Z (CTSZ), a lysosomal enzyme. In the study, UA lowered the levels of CTSZ, which were too high in AD mice.

“UA restored lysosomal functions in part by regulating cathepsin Z (Ctsz) protein.”

Brain inflammation is a big problem in Alzheimer’s. In this study, UA lowered levels of pro-inflammatory molecules, like:

• IL-1β
• TNFα
• MCP-1

It also raised levels of IL-10, a calming molecule that helps reduce inflammation. These changes show that UA can help calm the brain’s immune response.

UA raised levels of SIRT1 and SIRT3, proteins that protect mitochondria and fight aging. It also increased Parkin and BNIP3, proteins tied to mitophagy.

The treated mice also showed less DNA damage, a common issue in AD, by lowering markers like γ-H2AX and PARylation.

“UA induced sirtuin expression, mitophagy, and decreased DNA damage.”

Using NanoString gene panels, researchers found that UA reversed many Alzheimer’s-related gene changes. These genes were tied to:

• Immune system activity
• Synaptic function
• Lysosomal and mitochondrial pathways

This suggests that UA works on multiple levels—not just one part of the disease.

This study shows that Urolithin A could be a powerful tool against Alzheimer’s disease. It helps clean up brain waste, lowers inflammation, improves brain communication, and even rewires genes linked to AD.

UA is also safe in humans, as shown in earlier trials on muscle health. It crosses the blood-brain barrier and can reach brain cells directly.

If these results hold true in people, UA might offer a natural, well-tolerated therapy for slowing or possibly reversing parts of Alzheimer’s disease. It may also inspire new drugs that target mitophagy and lysosomal repair.

This scientific study shows that long-term Urolithin A treatment improves memory, reduces brain inflammation, and repairs the brain’s waste-clearing system in mice with Alzheimer’s disease. UA targets key issues that drive the disease by boosting mitophagy and restoring lysosomal function.

While this research was done in mice, the results are promising. Since Urolithin A is already proven safe in humans, it could be a valuable future therapy for Alzheimer’s, especially as part of a multi-targeted approach to protect brain health.