A group of Australian researchers have identified a potential drug target in the fight against dementia, Alzheimer’s disease and chronic traumatic encephalopathy (CTE), all diseases marked by the harmful aggregation of tau proteins.
In a previous study, the group showed in both animals and humans, that the neurotransmitter substance P profoundly increases after repeated mild traumatic brain injury (TBI). In the current study, published in Scientific Reports, the team successfully blocked substance P in mice with a specifically designed drug.
In an uninjured brain, normal tau promotes stabilization of microtubules with repeated rounds of phosphorylation and dephosphorylation to allow detachment and axonal transport. In a brain suffering from TBI, however, tau becomes hyperphosphorylated. This hyperphosphorylated version—which is more likely to aggregate—destabilizes microtubules and impairs axonal transport, which leads to the deterioration of synapses and, ultimately, retrograde degeneration.
Thus, the research team sought to identify a target that could reduce tau phosphorylation after TBI—and they found one in substance P.
In a mouse model, the researchers showed the administration of an NK1 antagonist, EUC-001, significantly reduced tau phosphorylation after a single moderate injury, as well as repeated mild TBI. EUC-001 worked best in those with repeated mild TBI—after 24 hours, the antagonist reversed all phosphorylation changes back to a non-injured resting state.
TBI is common among not only athletes, but military personnel, as well, after exposure to a blast. In a mouse model of mild blast-induced TBI, a significant increase in tau phosphorylation was recorded 28 days post-blast. Compared to the control, mice that were given the NK1 antagonist 30 minutes after injury had significantly reduced levels of tau phosphorylation at 28 days, back to pre-injury levels. Additionally, the NK1 antagonist seemed to improve neurological outcome on four common rodent tests.
Although there was a marked increase 28 days after injury, the team recorded no increase in tau phosphorylation 24 hours post-injury, signifying the harmful role tau plays as a secondary injury factor.
“The early tau oligomers are thought to be particularly toxic, acting as templates for the misfolding of native tau, seeding the spread of toxic tau species, as well as directly disrupting synaptic function,” the researchers explain in their paper. “Preventing acute alterations in tau phosphorylation may thus have long-term benefits after TBI.”
The researchers also identified three channels of transient receptor potential (TRP) that all promote substance P release. Targeting just one channel, TRPV1, the researchers found that the antagonist capsazepine significantly reduced tau phosphorylation 24 hours after injury—but only if taken 30 minutes prior to the injury event.
“Administering the TRPV1 antagonist 30 min after the [injury] had no effect on tau phosphorylation, suggesting that post-injury inhibition of TRP channels is of no benefit in halting the initiated injury cascade,” the researchers write.
The next step for this approach is human clinical trials, but the researchers anticipate that taking several more years as CTE can currently only be diagnosed post-mortem.
Photo: The red area shows where the brain becomes inflamed after concussion. Credit: University of South Australia