Natural Fruit, Vegetable Compound Blocks Alzheimer’s Disease in Mice

In research on mice engineered to develop AD symptoms less than one year after birth, a daily dose of the substance, a flavonol called fisetin, prevented the progressive memory and learning impairments associated with AD.

The agent, however, did not alter the formation of amyloid plaques in the brain, accumulations of proteins that are typically the culprit for AD development. The new finding suggests a way to treat AD symptoms independently of targeting amyloid plaques.

“We had already shown that in normal animals, fisetin can improve memory,” said Dr. Pamela Maher, a senior staff scientist in the Salk Institute for Biological Studies’ (La Jolla, CA, USA) cellular neurobiology laboratory who led the new study. “What we showed here is that it also can have an effect on animals prone to Alzheimer’s.”

Dr. Maher, more than 10 years ago, discovered that fisetin helps protect neurons in the brain from the effects of aging. She and her colleagues have since, in both isolated cell cultures and mouse studies, investigated how the substance has both antioxidant and anti-inflammatory effects on cells in the brain. Most recently, they discovered that fisetin activates a cellular pathway known to be involved in memory. “What we realized is that fisetin has a number of properties that we thought might be beneficial when it comes to Alzheimer’s,” said Dr. Maher.

Therefore, the scientists looked to a strain of mice that have mutations in two genes associated with AD. The researchers took a subset of these mice and, when they were only three months old, started to add fisetin to their food. The researchers, as the mice got older, tested their learning skills and memory with water mazes. By nine months of age, mice that had not received fisetin began performing more poorly in the mazes. Mice that had received a daily dose of the compound, however, performed as well as normal mice, at both nine months and one-year-old. “Even as the disease would have been progressing, the fisetin was able to continue preventing symptoms,” Dr. Maher commented.

In collaboration with scientists from the University of California, San Diego (USA), the scientists then examined the levels of different molecules in the brains of mice that had received doses of fisetin and those that had not. In mice with Alzheimer’s symptoms, they found, pathways involved in cellular inflammation were activated. In the animals that had taken fisetin, those pathways were dampened and anti-inflammatory molecules were present instead. One protein in particular, known as p35, was blocked from being cleaved into a shorter version when fisetin was taken. The shortened version of p35 is known to switch on and off many other molecular pathways. The study’s findings were published December 17, 2013, in the journal Aging Cell.

Studies on isolated tissue had hinted that fisetin might also decrease the number of amyloid plaques in AD affected brains. However, that observation was not evidenced in the mice studies. “Fisetin didn’t affect the plaques,” said Dr. Maher. “It seems to act on other pathways that haven't been seriously investigated in the past as therapeutic targets.”

Next, Dr. Maher’s team hopes to understand more of the molecular details on how fisetin affects memory, including whether there are targets other than p35. “It may be that compounds like this that have more than one target are most effective at treating Alzheimer’s disease,” stated Dr. Maher, “because it’s a complex disease where there are a lot of things going wrong.”

The scientists also aim to develop new studies to look at how the timing of fisetin doses affect its influence on Alzheimer’s. “The model that we used here was a preventive model,” explained Maher. “We started the mice on the drugs before they had any memory loss. But obviously human patients don’t go to the doctor until they are already having memory problems.”

The next phase of the research, therefore, in moving the discovery toward the clinic, according to the researchers, is to assess whether fisetin can reverse declines in memory once the processes have already started.

Related Links:
Salk Institute for Biological Studies
University of California, San Diego