Buck researchers get $3.4 million to look at a fruit-derived metabolite as a possible treatment for Alzheimer’s

Could a gut metabolite produced from dietary ellagic acid, which is abundant in strawberries, blackberries, cranberries, pomegranates and walnuts, help prevent or reverse Alzheimer’s disease? Buck professor Julie Andersen has received $3.4 million from the National Institutes of Health to answer that question in a mouse model of the disease.

But before you start proactively gorging yourself on berries and pomegranates in order to protect your memory, be aware that the production of that metabolite, urolithin A (UA), decreases with age due to microbial imbalances in the gut. You could overload on the good stuff without reaping much benefit.

Andersen will be looking at that aging issue in one of the most interesting aspects of the research. Her team will determine if rejuvenating the microbiome of older mice enhances the production of ellagic acid and whether that increases UA’s neuroprotective properties in lab animals.

The microbiome includes the vast collection of microorganisms that inhabit our gut. It’s a hot topic of research with imbalances linked to many disease processes, including neurodegeneration. “Most researchers are comparing individual microbiomes, trying to identify particular risk factors for Parkinson’s or other neurodegenerative diseases,” Andersen said. “We’re adding changes associated with aging and looking at whether this is one of the links between the brain and the gut.”

“This grant award highlights the Buck’s collaborative strength,” said Buck President and CEO Eric Verdin. “Looking at the gut microbiome through the lens of aging has broad implications for the health of older adults. I look forward to seeing the results of the work.” The five-year grant also includes the Tracy, Lithgow, Ramanathan and Schilling labs.

Autophagy: the mechanism at the heart of the study

Translated from Greek, autophagy literally means “self-eating.” It may sound gruesome but the natural process has great benefits for our cells. During autophagy, cells recycle damaged proteins and mitochondria and use them for nutrition. Andersen says there is an age-related decrease in autophagy in the brain. Given that Alzheimer’s pathology involves the accumulation of damaged proteins, she says many researchers are looking at ways to boost the recycling process as a way of preventing or treating the memory-robbing disease currently diagnosed in 5.7 million Americans.

Preliminary research in the Andersen and Lithgow labs involved several compounds, including UA, which increased activity in the major pathway involved in autophagy. Some of the compounds prevented Alzheimer’s, Parkinson’s, Huntington’s and Lou Gehrig’s disease symptoms in worm models of the diseases. These drugs also prevented Parkinson’s in middle-aged mice who were genetically fated to develop the disease. “We were particularly impressed with the efficacy of UA,” said Andersen. “And we liked the idea of boosting something that inherently protects the cells, but we have yet to unravel its full mechanism of action.”

For those interested in the scientific details: this research involves the transcription factor TFEB which is a master switch that turns on autophagy. This work will also focus on the farnesoid X receptor (FXR) which is traditionally expressed in the liver where it suppresses TFEB. Andersen says FXR has been found in brain neurons where its mechanisms remain unknown.

Going after Alzheimer’s

Alzheimer’s disease pathology primarily focuses on two proteins that go awry in the brain – amyloid beta and tau. Numerous drug trials aimed at clearing sticky amyloid plaques, which are a hallmark of the disease, have failed.  Efforts to address the tau-based neurofibrillary tangles associated with Alzheimer’s are ongoing but a clinical trial for a related tauopathy called PSP found no neuroprotective effects.  “It’s possible that both proteins need to be cleared in order to prevent or halt disease progression,” said Andersen.

The Buck research will involve mice which exhibit both of the major pathologies. Researchers will track neuropathology, loss of synaptic integrity, memory loss, and increased mortality in the UA-treated mice and their controls.

Research goals

“On one level, the research suggests that all the things we’ve heard about eating healthy foods are true and we’re providing one of the mechanisms by which they act,” Andersen said. “Understanding the mechanisms of UA-boosted autophagy could allow us to design drugs which do an even better job than food in activating the recycling process.”

The research will also determine if it’s possible to “rejuvenate” the gut of older mice by giving some of them the bacteria Clostridium leptum, which Andersen says appears to be essential for converting ellagic acid into UA. “If this enhances the neuroprotective effects of the ellagic acid, this could lead to probiotic support that people could buy over the counter.”

Back to the berries

Even though you might not be getting the full benefit of ellagic acid when you eat berries and pomegranates, there is no good reason to back off from enjoying them. These nutritional powerhouses are packed with vitamin C and other micronutrients that help the body deal with oxidative stress and inflammation (any maybe even wrinkles). They’re also loaded with heart-healthy soluble fiber which can help control cholesterol.