Fall 2012

Alzheimer’s Pathway

A single brain trauma affects an enzyme associated with the disease

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These cells used in Alzheimer's research have been engineered to produce amyloid plaques. Photo: Photo Researchers Inc.

A study performed in mice and using postmortem samples of brains from patients with Alzheimer’s disease found that a single moderate-to-severe traumatic brain injury (TBI) can disrupt proteins that regulate an enzyme associated with Alzheimer’s. The paper, published in The Journal of Neuroscience, identifies the complex mechanisms that result in a rapid and robust post-injury elevation of the enzyme, BACE1, in the brain.

The research may lead to the development of a drug that targets this mechanism and slows the progression of Alzheimer’s. As many as 5.1 million Americans suffer from Alzheimer’s.

“A moderate-to-severe TBI, or head trauma, is one of the strongest environmental risk factors for Alzheimer’s disease,” says first author Kendall Walker, a postdoctoral associate in the Department of Neuroscience at Tufts School of Medicine. “A serious TBI can lead to a dysfunction in the regulation of the enzyme BACE1. Elevations of this enzyme cause elevated levels of amyloid-beta, the key component of brain plaques associated with senility and Alzheimer’s disease,” she says.

Moderate-to-severe TBIs are caused most often by severe falls or motor vehicle accidents in which a victim loses consciousness. Not all head traumas result in a TBI. According to the Centers for Disease Control, 1.7 million people sustain a TBI every year. Concussions, the mildest form, account for about 75 percent of all TBIs. Studies have linked repeated head trauma to brain disease, and some previous studies have associated single events of brain trauma with brain disease, including Alzheimer’s.

Building on her previous work, Giuseppina Tesco, an assistant professor of neuroscience, led a research team that first used an in vivo model to determine how a single episode of TBI could alter the brain. In the acute phase (the first two days) following brain injury, researchers found reduced levels of two intracellular trafficking proteins, GGA1 and GGA3, and observed an elevation of BACE1 enzyme levels.

Next, in an analysis of postmortem brain samples from Alzheimer’s patients, the researchers found reduced GGA1 and GGA3 levels and elevated BACE1 levels in the brains of Alzheimer’s patients compared to the brains of people without Alzheimer’s, suggesting a possible inverse association.

In an additional experiment using a mouse strain genetically modified to express the reduced level of GGA3, the team found that a week after a traumatic brain injury, BACE1 and amyloid-beta levels remained elevated, even when GGA1 levels had returned to normal. The research suggests that reduced levels of GGA3 were solely responsible for the increase in BACE1 levels and therefore the sustained amyloid-beta production observed in the subacute phase, or seven days, after injury.

“When the proteins are at normal levels, they work as a clean-up crew for the brain by regulating the removal of BACE1 enzymes and facilitating their transport to lysosomes within brain cells, an area of the cell that breaks down and removes excess cellular material,” says Tesco. “BACE1 enzyme levels may be stabilized when levels of the two proteins are low, likely caused by an interruption in the natural disposal process of the enzyme.

“We found that GGA1 and GGA3 act synergistically to regulate BACE1 postinjury,” she says.

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