Like Alzheimer's disease, traumatic brain injury is sharply on the rise, though for different reasons: While Alzheimer's is increasing as the population ages, traumatic brain injury is increasing as industrialization puts motor vehicles – especially motorcycles – within reach of more people.
Now researchers from Georgetown University (Washington) have presented data showing that drugs that can treat the one condition may be useful in the other: beta and gamma secretases – the enzymes that, in Alzheimer's disease, process amyloid precursor protein into toxic A-beta peptides – appear to contribute to damage after traumatic brain injuries, as well.
Head injury victims have an increased risk of developing Alzheimer's disease, and in autopsies, amyloid plaques – usually the anatomical hallmark of Alzheimer's – have been found in young people and even children. Senior author Mark Burns said his team's current work – which is published in the March 15 issue of Nature Medicine – shows that "the same pathways activated chronically in Alzheimer's disease are activated acutely in traumatic brain injury."
Burns and his colleagues looked at the role of both beta-and gamma secretases in traumatic brain injury, but in different ways. To test the effects of beta-secretase, they compared normal mice with BACE1 knockouts, which lack the beta-secretase gene. For the effects of gamma secretase they used the pharmacological inhibitor DAPT. While there are pharmacological inhibitors of beta-secretases as well, "the ones that we can get our hands on do not cross the blood-brain barrier," Burns, an assistant professor at Georgetown University Medical Center, told Medical Device Daily's sister publication, BioWorld Today.
Though amyloid plaques start forming very rapidly after traumatic brain injury – they can be seen within a day after an injury in animal studies – Burns and his colleagues waited until two to three weeks after inducing brain injuries to test for the effects of reduced secretase activity. The reason, Burns explained, is that though head trauma causes immediate brain injury, it also initiates secondary injury which "continues to cause damage for at least two weeks."
During this time, "cell damage continues to spread, and neurons continue to die." Behaviorally, while brain injury leads to immediate deficiencies in fine motor coordination, memory impairment develops more slowly, and over a longer period of time.
When they tested the effects of blocking with kind of secretase activity, they found that two weeks after the injury, BACE1-knockouts as well as those treated with DAPT showed better fine motor coordination and spatial memory than control animals. The swimming speed of the animals was not affected. Using magnetic resonance imaging, the authors showed that animals with reduced secretase activity had fewer neurons die after brain injury, particularly in the hippocampus, a structure important for learning and memory that is particularly affected by the second wave of neuronal death. In their paper, Burns and his colleagues note that while BACE1 knockouts, of course, chronically lack the beta-secretase gene, "the gamma-secretase inhibitor was administered after trauma, modeling a clinically relevant situation."
Burns said that his own team plans to focus mainly on the mechanistic side of how secretases prevent the second wave of damage after an injury. But he added that he would "love" to see the approach make in into clinical trials, and that secretases have a somewhat simplified path to the clinic, given that they are already in clinical trials for Alzheimer's disease.