International Business Department           Liu Bojia           June 03, 2023

  Alzheimer's disease (AD) has become one of the key disease types affecting the health of the elderly population, with studies predicting that by 2050, the global population of AD patients will reach 153 million, about three times the number of patients today. As a result, scientists are constantly searching for new strategies that can effectively prevent and treat AD.

  According to the mechanisms discovered in existing studies, the occurrence of AD is related to the formation of plaques of beta amyloid, as well as abnormal tau protein tangles. In addition, physiological changes associated with aging itself are also important factors driving the development of AD, such as neuroinflammation, cellular autophagy damage, and mitochondrial dysfunction. When mitochondrial autophagy (mitophagy) is faulty, it can lead to a buildup of excessively large and abnormal mitochondria that can sustain damage to neuronal cells, and abnormal mitochondrial autophagy is frequently observed in the brain cells of AD model mice.

  And recent research published in Alzheimer's & Dementia has found that ingredients from pomegranates and strawberries may help with mitochondrial autophagy. These fruits are rich in ellagitannins and ellagic acid, which, when ingested, can be converted by gut bacteria into urolithin A (UA), which happens to be able to stimulate mitochondrial autophagy and reduce the associated inflammatory damage to neuronal cells, improving cognitive function in AD mice.

  This is not the first time that a study has identified physiological benefits from UA, as a paper in Nature Aging last year showed that UA can act as a mitochondrial regulator for restoring the blood reconstitution capacity of senescent haematopoietic stem cells, and that direct supplementation with UA restored lymphangiogenesis in senescent mice, enhancing their resistance to viral infections.

  In addition, the Cancer Research Institute in Frankfurt, Germany, has also published an article in the journal Immunity stating that UA can regulate the function of immune cells and increase their ability to fight cancer. Mice supplemented with UA while ingesting carcinogens can have a lower incidence of tumours in them, and tumours that have already been created will be smaller in size.

  Going back to the latest paper, a team of researchers from the University of Copenhagen constructed a group of AD model mice in their experiments, which gradually develop AD-related pathological features. However, damage to mitochondrial autophagy often precedes the onset of pathological symptoms, and for this reason the authors started a group of mice on UA treatment at a very young age.

  After five months of continuous treatment, all AD model mice participated in a variety of behavioural tests, and mice in the UA-treated group could find hidden platforms and get out of mazes faster than mice with AD without any treatment, but there was no difference in swimming speed between the two groups, suggesting that UA improves learning beyond movement and also boosts memory function.

  In addition to early intervention being effective, the authors found that long-term treatment with UA after the onset of AD symptoms also enhanced cognitive function in mice, and the olfactory dysfunction that accompanies AD was similarly improved. According to the results of the analysis, AD mice treated with UA showed a slowdown in the accumulation of beta amyloid in the brain and a significant reduction in the level of abnormal phosphorylation of tau proteins.

  The authors also observed that UA inhibited the production of histatinase Z, an enzyme that tends to be overactive in AD individuals and causes neuroinflammation. In addition, lysosomal function as well as mitochondrial autophagy were restored in hippocampal tissue following UA treatment, with increased expression of mitochondrial autophagy-associated proteins in neuronal cells on long-term UA, along with a decrease in the DNA damage response. The authors concluded that these changes restored the ability of nerve cells to process waste products, leading to an improvement in AD symptoms.

  Of course, the authors also emphasise that the levels of UA used in the experiment could not be achieved by consuming pomegranate alone. ‘The exact safe and effective dose still needs to be confirmed by more trials, but I think it's certainly not just one pomegranate a day that will do the trick,’ said Professor Vilhelm Bohr, the study's corresponding author, who pointed out that there are now a number of pill-forms of UA that can be taken orally, and a number of related clinical trials underway that also holds potential promise for the search for therapies for UA prevention and treatment of AD.