New research indicates that just one traumatic injury to the brain can lead to Alzheimer’s disease.
The study, 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. And these results, perhaps, will lead to the development of a drug treatment that targets this mechanism to slow the progression of Alzheimer’s disease.
The research was performed in mice and on postmortem samples of brains from patients with Alzheimer’s disease. It found that a single event of a moderate-to-severe traumatic brain injury (TBI) can disrupt proteins that regulate an enzyme associated with Alzheimer’s.
“A moderate-to-severe TBI, or head trauma, is one of the strongest environmental risk factors for Alzheimer’s disease,” first author Kendall Walker, a postdoctoral associate in the department of neuroscience at Tufts University School of Medicine (TUSM), said in a statement.
“A serious TBI can lead to a dysfunction in the regulation of the enzyme BACE1,” Walker said. “Elevations of this enzyme cause elevated levels of amyloid-beta , the key component of brain plaques associated with senility and Alzheimer’s disease.”
TUSM neuroscientist Dr. Giuseppina Tesco 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 (first two days) following injury, levels of two intracellular trafficking proteins (GGA1 and GGA3) were reduced, and a elevation of BACE1 enzyme level was observed, according to a TUSM press release.
In an analysis of postmortem brain samples from Alzheimer’s patients, researchers found that GGA1 and GGA3 levels were reduced while BACE1 levels were elevated in the brains of Alzheimer’s disease patients compared to the brains of people without Alzheimer’s disease, suggesting a possible inverse association.
In an additional experiment using a mouse strain genetically modified to express the reduced level of GGA3 that was observed in the brains of Alzheimer’s disease patients, the team found that one week following 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 BACE 1 levels and therefore the sustained amyloid-beta production observed in the sub-acute 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,” Tesco said in a statement.
“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,” she said.
“We found that GGA1 and GGA3 act synergistically to regulate BACE1 post-injury,” Tesco continued. “The identification of this interaction may provide a drug target to therapeutically regulate the BACE1 enzyme and reduce the deposition of amyloid-beta in Alzheimer’s patients. Our next steps are to confirm these findings in postmortem brain samples from patients with moderate-to-severe traumatic brain injuries.”
Moderate-to-severe TBI are typically caused by traumas, such as severe falls or motor vehicle accidents, that result in a loss of consciousness.
This study was supported by grants from the National Institute on Aging, part of the National Institutes of Health; and a grant from the Cure Alzheimer’s Fund.
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