Traumatic brain injuries, whether they occur on a sports field or in a war zone, are on the rise.
What's worse, these head traumas have been linked to long-term neurodegenerative diseases, notably Alzheimer's and a condition known as chronic traumatic encephalopathy, or CTE.
Now, a team of researchers report they've discovered the "missing link" between traumatic brain injuries and these degenerative brain diseases and developed a special antibody that may help prevent the conditions — at least in mice.
In a study published online in the journal Nature, researchers at Beth Israel Deaconess Medical Center identify the "missing link" culprit as "cis P-tau, a misshapen and toxic species of tau protein that has not been previously identified," says Kun Ping Lu, MD, PhD, the study's co-senior author and chief of the Division of Translational Therapeutics in the Department of Medicine at BIDMC and professor of medicine at Harvard Medical School.
Lu, in an interview, explains how these toxic proteins can build up in the brain and start causing serious damage after repeated head injuries:
A single concussion, a mild traumatic brain injury (TBI), results in moderate induction of cis P-tau, which returns to the baseline within 2 weeks. However, repetitive concussions, as might occur in contact sports, result in robust induction of cis P-tau that is persistent for months in mouse brains. This is similar to what is produced following a single severe TBI caused by a blast, as seen in military blast, or an impact, as seen in a severe car accident. Strikingly, cis P-tau is produced as soon as 12 hours after TBI, setting in motion the destructive course of events that leads to Alzheimer’s and CTE.
cis P-tau protein is extremely neurotoxic, disrupting neuron structure and function, progressively spreading to other neurons throughout the brain over time, leading to neuron death. Therefore, cis P-tau has the ability to kill one neuron after another in the brain over time, eventually leading to Alzheimer’s and CTE. These results in animal models are consistent with clinical observations that either repetitive concussions or single severe TBI can lead to Alzheimer’s or CTE.
Importantly, our cis antibody is not only able to spot only the toxic cis P-tau, but also to neutralize its toxicity to neurons. As a result, treating TBI mice with cis antibody can stop brain damage after TBI and prevent its debilitating long-term consequence of Alzheimer’s and CTE. Thus, cis P-tau is an early driver of TBI and its related Alzheimer’s disease and CTE, which can be effectively blocked by antibody therapy.
The immediate implications of these findings are to emphasize TBI prevention; however, if concussion occurs, it is critically important to allow the body defense system to remove the toxic tau protein completely before another concussion occurs. The most exciting development will be to humanize our current monoclonal antibody to develop early intervention to treat TBI and to prevent Alzheimer’s disease and CTE, which can be done within next a few years. In addition, because the same toxic tau protein also destroys brain cells in Alzheimer’s, this early intervention may be used to treat this most common form of dementia in older individuals.
The BIDMC release also states that "Lu and Zhou have interests in Pinteon Therapeutics, Inc., which has licensed Pin 1 technology from BIDMC."
Clearly, more work must be done for this therapy to be useful in humans. Still, the problem is pervasive: Alzheimer’s is the most common form of dementia in older individuals and currently affects more than 5 million Americans and 30 million people worldwide, researchers note, while CTE, which can also lead to progressive dementia, is a degenerative brain disease associated with a number of neurological symptoms including risk-taking, aggression and depression.
Here's more background from the BIDMC news release:
“Healthy tau protein is found in the brain and serves to assemble and support microtubules, the ‘scaffolding systems’ that give neurons their unique shape and are integral to memory and normal brain functioning,” explained Lu. But in Alzheimer’s, CTE and other neurodegenerative diseases, collectively called tauopathies, tau becomes tangled and unable to function properly.
“Recent studies of CTE in the brains of boxers, American football players and blast-exposed veterans have identified extensive neurofibrillary tau tangles,” he said. “But, because these tangles were not detected until months or, more likely, years after TBI, it has not been known whether tauopathy is a cause or a consequence of TBI-related neurodegenerative disease. We have now shown that it is a cause of these diseases.”
Co-senior author of the new study Xiao Zhen Zhou, MD, also an investigator in BIDMC’s Division of Translational Therapeutics and Assistant Professor of Medicine at HMS, had previously developed polyclonal antibodies capable of distinguishing between two distinct isoforms of the phosphorylated tau protein. The isoform known as trans is in a relaxed shape and is important for normal brain functioning. The other isoform, known as cis, is in a twisted shape and is prone to becoming tangled. Cis P-tau is an early pathogenic protein leading to tauopathy and memory loss in Alzheimer’s disease.
“In this new study, we wanted to find out whether cis P-tau is present following TBI and, if so, how to eliminate it from the brain without disrupting the healthy functioning of trans P-tau,” said Zhou. “We generated a monoclonal antibody able to detect and eliminate cis P-tau very early in the disease process.”
Monoclonal antibody technology is a popular drug development approach. Working like a lock and key, it enabled the investigators to both detect and neutralize only the toxic cis P-tau.
After confirming the existence of this toxic cis tau isoform in the brain tissue of humans who had died of CTE, the authors simulated contact-sport and blast-related injuries in mouse models, and found that the brain’s induction of cis P-tau is dependent on injury severity and frequency.
“Mild TBI, also known as a concussion, results in moderate and transient cis P-tau induction,” explained Lu. “However, repetitive concussions, as might occur in contact sports, can result in robust and persistent cis P-tau induction. This is similar to what is produced following a single severe TBI caused by a blast or impact.”
Subsequent experiments revealed that the cis P-tau protein disrupts the brain’s microtubule scaffolding systems and the transport of mitochondria, the powerhouse that provides energy for neuronal function, and eventually leads to neuron death by apoptosis. The research also showed that, over time, cis P-tau progressively spreads throughout the brain. Treating TBI with cis antibody eliminated the toxic cis P-tau, prevented widespread tauopathy and neuron death and restored brain structure and function...
“Alzheimer’s disease and chronic traumatic encephalopathy are terrible diseases that progressively rob individuals of their memory, judgment and ability to function,” said study coauthor Alvaro Pascual-Leone, MD, PhD, Chief of the Division of Cognitive Neurology at BIDMC and Professor of Neurology at HMS. Pascual-Leone also serves as Associate Director of the Football Players Health Study (FPHS) at Harvard University, a multi-year initiative to discover new approaches to diagnose, treat and prevent injuries in professional football players.
“High-profile cases of CTE, such as that of the late football player Junior Seau, have vividly demonstrated the tragic consequences of this affliction,” he added. “We need to learn more about CTE’s causes in order to develop better ways of diagnosing and treating it, and this study offers us a promising early intervention to prevent the pathologic consequences of this disease. These findings additionally offer us a new way to approach Alzheimer’s disease, which poses a staggering unsustainable burden throughout the world. Alzheimer’s afflicts both individuals and their families and, it deprives society of the contributions of experienced and wise elders.”
Nature release: A newly devised antibody therapy can reverse some of the pathological changes that occur after traumatic brain injury (TBI) in mice, suggests a study published in Nature this week. Further research is needed to establish how the findings may translate to humans.
When mice and humans are exposed to TBI, neurons in the brain begin to produce phosphorylated tau protein (cis P-tau), Kun Ping Lu and colleagues show. In mice, this causes disruption to the cells’ internal scaffolding, spreads to other neurons, and leads to massive cell death. However, the authors find that treating mice with a specially created antibody against cis P-tau can prevent these changes.
Traumatic brain injury, such as that caused by contact sports or military-related incidents, is a major cause of death and disability in children and young adults. It is linked with long-term neurodegenerative conditions, such as Alzheimer’s disease, which also feature abnormal tau proteins. In this study, mice respond quickly to the antibody — positive changes to the brain were seen within days. Additional work is needed to evaluate whether the results may have therapeutic implications, but the authors suggest that in humans the antibody therapy may ameliorate the short-term consequences of TBI and could potentially help prevent any longer term neurodegenerative repercussions.