10:56am Tuesday 31 March 2020

Mechanisms of Alzheimer’s Disease Found in Fly and Mouse Studies

Both studies, led by Grace Zhai, Ph.D., assistant professor of molecular and cellular pharmacology, and pharmacology graduate student Yousuf Ali, Ph.D., are published back-to-back in Human Molecular Genetics, a journal normally focused on discoveries in humans. The study with fruit flies was deemed so noteworthy that it was selected as the cover story of the January 15 issue.

“Our studies in both fly and mouse models describe a potential mechanism of neurodegeneration in a form of Alzheimer’s disease and a neuroprotective factor that could protect against and delay the onset of neurodegeneration,” says Zhai.

Building on a study published in Nature in 2008, Zhai and her team discovered that a neuroprotective factor (NMNAT) protects against tauopathy in both fly and mouse models. Tauopathies are a group of neurodegenerative diseases, including Alzheimer’s, which are characterized by a build-up of tau proteins that lead to neurofibrillary tangles, a common hallmark of the disease.

In the first study using fruit flies, the scientists showed that NMNAT suppresses neurodegeneration by promoting the clearance of excess tau proteins that were in toxic forms.

In the second study, the team, which included collaborators from Baylor College of Medicine in Texas, went a step further by demonstrating that part of the mechanism of tau-induced neurodegeneration is through a reduced amount of NMNAT. Overexpressing NMNAT in mice proved to have a neuroprotective effect. Zhai says the team is “the first to show that NMNAT level is a critical determinant of the onset and severity of degeneration.”

Zhai works primarily with fruit flies, Drosophila, because of their unique characteristics: basic cellular and molecular mechanisms, brain neurocircuitry similar to humans, and a life span of less than two months providing rapid information.

Mutant flies are created in the laboratory by introducing DNA carrying a mutation of the disease to be studied. In this case, it was a mutation for frontal temporal dementia. Zhai’s work with flies soon after her arrival at the Miller School in 2007 uncovered the neuroprotective qualities of the protein NMNAT. The current studies confirmed that NMNAT protects against a broad spectrum of neurodegenerative conditions including tauopathy.

NMNAT occurs naturally in the body to help neurons stay healthy. Zhai’s team discovered that when neurodegeneration occurs, NMNAT is reduced. Further, the scientists found that by increasing the expression of NMNAT, much of the dementia-related behavior could be normalized, even with the presence of the degeneration-inducing mutation.

Zhai says that because the discovery was made in flies first and then confirmed in mouse models, their research advances the field substantially. “This is the first time that studies in flies and in mice appear side-by-side addressing the same disease.”

The next step is discovering how to translate this finding into a therapy for neurodegenerative diseases. Several pharmaceutical companies have shown interest in testing drugs that enhance NMNAT expression. That will fall to another group of scientists. For Zhai, she will turn again to her Drosophila, in the hopes of discovering the complex mechanisms underlying neurodegeneration.

University of Miami,

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