Four years ago, a research group at the University of Oslo made what would turn out to be a major discovery. They found that an extract from passion fruit had the potential to slow the development of Alzheimer’s disease. What is it about this small fruit that might promote healthy ageing and slow the progression of dementia? The researchers have now made an exciting new discovery that could significantly accelerate the search for a medicine against Alzheimer’s disease. “After four years of hard work, we have managed to uncover what the passion fruit’s secret is,” says Associate Professor Evandro Fei Fang‑Stavem at the University of Oslo and Akershus University Hospital.

Inside passion fruit there is a molecule called alpha‑amyrin, α‑amyrin for short. It appears to have some very special properties. “Our study shows that alpha‑amyrin has the ability to protect some absolutely central processes in the brain. And we believe that we may be able to use this molecule in a medicine against Alzheimer’s disease if it also works in future clinical trials against this difficult-to-treat disease,” says Fang‑Stavem. The study has been published in the journal Advanced Science.

Alpha-amyrin acts as a “brain guardian”
Alzheimer’s disease is a disorder of the brain that develops slowly over several years. It is the most common cause of dementia. People who develop the disease experience memory problems, struggle with language and may have difficulty finding their way. They also often undergo changes in personality. The disease is caused by a build‑up of waste products in the brain. This “rubbish” consists of proteins, which damage nerve cells and eventually cause them to die. “Alpha‑amyrin acts like a kind of “brain guardian”, making sure that this rubbish does not build up,” explains postdoctoral fellow Dr. Shu‑qin Cao, a 1^st author of this study from the University of Oslo.

Brain cells are vulnerable to changes that occur as we age
Our brain needs a great deal of energy to function properly. When waste products accumulate in the brain, the brain’s energy factories are no longer able to produce enough energy. These energy factories are called mitochondria, which are sub-cellular organelles found in almost all our cells. As we grow older, the cells in the brain are not always able to clear away this waste. “Our brain cells are vulnerable to the changes that take place in the body as we age. They depend on the mitochondria producing enough energy, but this system does not work as well when waste products build up,” explains Cao, and continues: “So, the fact that alpha‑amyrin found in passion fruit actually protects the mitochondria is a major finding.”

Mice with Alzheimer’s had better memory when given supplements
In the study, the researchers examined what happened when mice with Alzheimer’s disease were given supplements of alpha‑amyrin. They observed that fewer waste products accumulated. The mice also performed better in memory tests. “Alpha‑amyrin supported the brain’s own control system and helped the cells to remove the rubbish and avoided inflammatory environments, so that the mitochondria could function normally,” says Cao.

How does alpha‑amyrin work?
The researchers also investigated why the molecule found in passion fruit protects the mitochondria. Among other things, they discovered that alpha‑amyrin modulates DLK-SARM1-ULK1 cascade to promote ULK1 activiation. They believe this is one of the underlying mechanisms that explains how the molecule protects the brain. “The protein ULK1 has an important role in mitochondrial quality control by jinitiating autophagy and facilitating the removal of damaged mitochondria,” Cao explains. In addition, the researchers also found that alpha‑amyrin remains in the bloodstream long enough to function as the active ingredient in a future medicine. They tested this in young, healthy mice. “We also saw that the molecule is able to move from the bloodstream into the brain in these mice, which indicates that it is possible to get the molecule to reach the brain,” she says.

The food you eat today may affect your brain health in the future
Passion fruit is not the only type of fruit that contains alpha‑amyrin. It is also found in a number of other colourful fruits and vegetables, such as tomatoes and American/European Cranberry. “We know from previous research that eating colourful fruit and vegetables is good for the brain. Now we see that these benefits are likely to come from natural ingredients found in this kind of fruit and vegetables, especially in passion fruit. These ingredients protect the mitochondria and help preserve memory. Although we need more research, we can say that there is increasing research‑based evidence that what we eat today can influence our brain health many years into the future,” says postdoctoral fellow Dr. Shu‑qin Cao, a 1^st author of this study from the University of Oslo.

The researchers believe they are on the trail of a possible future medicine for Alzheimer’s
The researchers behind the study believe they are on the trail of a possible future medicine for Alzheimer’s disease. "We would like bring our investigations of alpha-amyrin further, such as to perform clinical trials on its bioavailability, safety, and efficacy against dementia, when funding and resources are available", Cao explains. Indeed, the researchers are moving forward towards this direction. Indeed, through the UiO's Technology Transfer Office (TTO) Inven2 AS, UiO has licenced commercial development of alpha‑amyrin to a Hong Kong-based company, the HK LONGEVITY SCIENCE LABORATORY.
The researchers also investigated correlation between high consumption of colourful and nutritional fruits and vegetables and the risk of dementia in the human population, and they used a 10-year epidemiological data. "Our epidemiological data undoubtedly indicate that high consumption of colourful and nutritional fruits, such as passion fruit, correlates with low dementia risk; and our 5-year preclinical study, led by Cao, has unveiled the mechanisms on why a passion fruit molecule can forestall dementia progression in animal and stem cell models of Alzheimer," Fang-Stavem concludes.

An international collaboration
This project was initiated and lead by Prof. Evandro Fei Fang-Stavem, with first author Dr. Shu-qin Cao, both from the University of Oslo. Co-leaders of this project were Prof. Patricia Boya (University of Fribourg, Fribourg, Switzerland) and Prof. Tewin Tencomnao (Chulalongkorn University, Pathum Wan, Bangkok, Thailand). A co-first author was Dr. Juan Ignacio Jiménez-Loygorri (Spanish National Research Council, Madrid, Madrid, Spain). Other key collaborators of this project were Prof. Ding Ding (Huashan Hospital, Fudan University, China), Prof. Cornelia van Duijn (The University of Oxford, Oxford, UK), and Prof. Nektarios Tavernarakis (University of Crete, Heraklion, Crete, Greece).