Using fruit flies that are genetically engineered to imitate the molecular symptoms of human dementia, UCLA neurologists identified a new way that the disease kills brain cells. Reported in the May 16 issue of Neuron, the findings suggest that the fly model could inexpensively speed the development of drugs to treat Alzheimer's disease.
"Unlike mice, fruit flies are inexpensive to breed and care for," said Dr. George Jackson, principal investigator and UCLA assistant professor of neurology. "They also multiply quickly, allowing scientists to test hundreds of scenarios simultaneously and to reach conclusions more quickly. All of these variables make them ideal for genetic research on dementia."
In Alzheimer's and other neurodegenerative diseases, a cellular protein called tau creates abnormal "tangles" in the brain. Magnification of the tangles shows that the tau protein changes when phosphates attach to its surface. But scientists have been puzzled by whether the altered tau forms the tangles or if the modification is merely a byproduct of cellular breakdown.
"Does the altered tau cause the tangles – or do the tangles cause the alteration?" asked Jackson. "It's the old chicken and the egg question. We created a fruit fly model to find out."
Jackson's team bred fruit flies that were genetically altered to produce human tau in their eyes. Examining the flies' eyes under the microscope, the scientists observed that the cells developed abnormally and rapidly died.
"The retina opens a window into the brain," said Jackson. "These findings imply that there is indeed a causal relationship between tau modification and cell death."
Searching for a genetic pathway that may serve as a potential drug target, the UCLA team decided to evaluate other proteins' influence on the nerve cells' death. They discovered that manipulation of the "wingless pathway" — a group of genes responsible for mapping early brain development in both humans and flies – significantly affected cellular degeneration.
In particular, "shaggy" — a fly gene in the wingless pathway that interacts with human tau — demonstrated the greatest effect.
"We found that increasing the amount of shaggy worsened degeneration of the nerve cells," explained Dr. Daniel Geschwind, co-author and UCLA assistant professor of neurology. "In contrast, reducing the amount of shaggy improved cellular degeneration."
Serendipitously, the scientists' increase of shaggy led them to the study's most significant breakthrough. For the first time, tau-laced tangles and filaments resembling those found in the brains of Alzheimer's patients began appearing in the flies' eyes.
"When we combined increased amounts of shaggy and human tau in the fly's eye, we saw abnormal tangles that looked strikingly similar to those seen in the brains of dementia patients – even on the microscopic level," said Geschwind.
"We think this discovery could provide an important tool for testing future therapies to treat Alzheimer's and other neurodegenerative disorders," he emphasized.