The Effects of Urolithin A on Mitochondria in Early Alzheimer's Disease

This scientific summary is based on the scientific article titled Effects of Urolithin A on Mitochondrial Parameters in a Cellular Model of Early Alzheimer Disease, by Carsten Esselun et al., which explores the potential neuroprotective properties of Urolithin A (UA), a metabolite derived from ellagitannins found in pomegranates and walnuts. The study investigates how UA influences mitochondrial function in SH-SY5Y neuroblastoma cells, particularly those modified to mimic early Alzheimer's disease (SH-SY5Y-APP695). The authors assess various mitochondrial parameters, including respiration, membrane potential, ATP production, autophagy, and reactive oxygen species (ROS) levels, alongside gene expression related to mitochondrial biogenesis and function.

Urolithin A is made in our gut when we eat foods like pomegranates and walnuts. Alzheimer's disease affects the brain, causing memory loss and confusion.

Mitochondria, the powerhouses of cells, are essential for aging and brain health. This study looks at how Urolithin A helps protect mitochondria in the early stages of Alzheimer's.

The study explored how Urolithin A affects mitochondria in early Alzheimer's.

Researchers used SH-SY5Y cells, a type of human neuroblastoma cell commonly used as a model for neuronal function and development. To create a model for early Alzheimer's disease, some of these cells were genetically modified to express the amyloid precursor protein (APP695), resulting in the SH-SY5Y-APP695 cell line.

This modification leads to the production of amyloid-beta peptide, which is associated with Alzheimer's pathology. The unmodified SH-SY5Y cells, referred to as SH-SY5Ymock, were used as controls.

The researchers conducted a series of experiments to assess the impact of Urolithin A on mitochondrial function and related cellular processes:

• Mitochondrial Respiration (Energy Production): They measured the oxygen consumption rate to evaluate how well mitochondria produced energy through oxidative phosphorylation (OXPHOS). "Treatment with 1 µM UA did not alter the respiration of SH-SY5Ymock cells...uncoupled CII and CIV respiration were significantly reduced by UA treatment in SH-SY5Y-APP695 cells."
• Mitochondrial Membrane Potential (MMP): MMP is an indicator of mitochondrial health and function. The researchers assessed MMP using rhodamine-123 fluorescence. "Treatment with a 10-fold increased UA concentration (10 µM) significantly reduced MMP."
• ATP Levels (Cell Energy): They measured adenosine triphosphate (ATP) levels to determine the energy available within the cells. "Examination of ATP levels revealed that treatment with 1 µM UA did not affect either parameter in the two cell lines...a similar trend was observed for the ATP concentration."
• Autophagy (Cell Cleanup): Autophagy is the process of removing damaged components. The study used Western blotting and fluorescence assays to assess levels of autophagy markers such as LC3B-I, LC3B-II, and p62. "LC3B-I, LC3B-II, and p62 levels were unchanged."
• Reactive Oxygen Species (ROS) Levels: ROS are indicators of oxidative stress within cells. The researchers measured ROS using DCFDA/H2DCFDA fluorescence. "Treatment with 1 µM UA for 24 h did not affect ROS production."
• Gene Expression Related to Mitochondria: Using quantitative real-time PCR (qRT-PCR), they analyzed the expression of genes involved in mitochondrial bioenergetics, biogenesis, and autophagy. "UA treatment significantly increased expression of genes for mitochondrial biogenesis and OXPHOS."

The study found several vital effects of Urolithin A on mitochondria.

Mitochondrial Function

At 1 µM, Urolithin A did not change respiration or ATP levels but did at 10 µM. "Treatment of cells with UA (1 µM) for 24 h did not affect ROS production or levels of Aβ, but significantly increased expression of genes for mitochondrial biogenesis and OXPHOS."

Gene Expression

Urolithin A increased the expression of genes related to mitochondrial biogenesis and function, especially in SH-SY5Y-APP695 cells.

Autophagy and ROS

Urolithin A did not significantly impact autophagy markers like LC3B-I, LC3B-II, and p62, or ROS levels.

Amyloid Beta Levels

Treatment with Urolithin A did not affect the levels of amyloid beta, a protein linked to Alzheimer's disease.

1. Mitochondrial Respiration and ATP Production: Urolithin A at 1 µM did not change respiration or ATP levels. At 10 µM, there was a decrease in MMP and ATP, suggesting high doses might be harmful. "When cells were treated with a 10-fold increased UA concentration (10 µM), MMP was significantly reduced and a similar trend was observed for the ATP concentration."
2. Mitochondrial Membrane Potential (MMP): MMP measures the health of mitochondrial membranes. Higher doses of Urolithin A reduced MMP, which could be toxic.
3. Autophagy Markers: Autophagy is how cells clean out damaged parts. Urolithin A did not significantly change autophagy markers like LC3B-I, LC3B-II, and p62. "LC3B-I, LC3B-II, and p62 levels were unchanged."
4. Gene Expression for Biogenesis: Urolithin A increased the expression of several genes related to mitochondrial biogenesis, like TFAM and NDUFV1, especially in Alzheimer's model cells. "Mitochondrial Transcription Factor A (TFAM) expression was specifically increased in SH-SY5Y-APP695."

The study explains how Urolithin A could help treat Alzheimer's disease.

• Potential Benefits: Urolithin A may help keep mitochondria healthy and support new mitochondria production. "Data suggests that biogenesis might be facilitated by estrogen-related receptor (ESRR) genes."
• Need for Further Research: More studies are needed to fully understand its effects and potential as a treatment option.
• Therapeutic Potential: While Urolithin A shows promise in gene expression related to mitochondrial health, its direct impact on Alzheimer's' symptoms needs more study. "UA shows no effect on autophagy in SH-SY5Y-APP695 cells and its effect on mitochondrial function is limited."

Urolithin A supports mitochondrial health by changing gene expression related to mitochondrial biogenesis. Its effects on mitochondrial function in Alzheimer's cells are complex and depend on the dose.

More research is needed to see if it can be a treatment for neurodegenerative diseases like Alzheimer's. "Data suggests that UA treatment induces hormetic effects as it induces transcription of several genes related to mitochondrial biogenesis."