Formation of Tau Prions in Transgenic Mice Following Traumatic Brain Injury
Stanley B. Prusiner, M.D.
University of California, San Francisco, San Francisco, CA, Departement of Neurology
Clinical Neuroscience Research
April 2013, for 3 years
Creating a chronic traumatic encephalopathy animal model to speed human disease understanding
Chronic traumatic encephalopathy (CTE) is a progressive degenerative brain disease that results from repetitive “closed” head trauma and produces symptoms that range from problems with attention, concentration, disorientation, and depression to memory loss and dementia. In CTE, the skull is not damaged but brain tissue deteriorates as harmful abnormal proteins, called “tau prions,” accumulate in and eventually kill brain cells. Tau prions are formed from normal tau proteins in the brain that mis-fold and, though a self-propagating process, induce nearby tau proteins to similarly mis-fold. Affected brain cells release their aggregated tau that is then taken up by nearby brain cells. As tau prions aggregate within brain cells, they form “neurofibulary tangles” that impede cell-to-cell communication. This process continues to spread in the brain, impeding brain cell communication and causing cells to degenerate and die. The variation in CTE symptoms, therefore, depends upon where in the brain, and how severely, tau-induced degeneration occurs.
For demonstrating this biological principle of infection in sheep with the degenerative disease “scrapie” and its human variant called Creutzfeldt-Jakob disease, Stanley Prusiner, M.D., was awarded the Nobel Prize in 1997. He termed the abnormal proteins prions. CTE is among several degenerative diseases produced by tau prions, referred to as “tauopathies.” CTE is increasingly being recognized in troops exposed to blast-wave concussions and in athletes engaged in football, soccer, boxing and wrestling. Evidence that CTE is produced by tau prions came from recent autopsy studies of a large series of brains of deceased soldiers and athletes who had been exposed during life to repeated head trauma. Effective treatment for people with CTE, as for other tauopathies, is lacking largely because tau prions cannot yet be imaged in the human brain to assess experimental treatment effects.
Development of a CTE animal model where tau could be imaged is therefore a vital first step and will be undertaken by Dr. Prusiner, who has continued to advance progress in understanding prion diseases and in seeking effective treatments for them. Thereafter, in a planned second-phase study, Dr. Prusiner and colleagues will seek to determine CTE tau prion levels and distribution in the mouse brain. These studies are expected to provide the opportunity to evaluate experimental therapies’ abilities to prevent, slow or reduce tau accumulation in the animal brain and then test those that show promise in CTE patients.
Additionally, the research may lead to development and testing of therapies for other tauopathies, which include fronto-temporal dementias, such as Pick’s disease and progressive supranuclear palsy. In addition, the studies may have implications for degenerative diseases that involve tau. The best known of these diseases is Alzheimer’s disease, where tau prions accumulate within cells while an abnormal peptide called “amyloid” builds up around cells and produces plaques. The prion-like spread of tau aggregates in Alzheimer’s begins in the entorhinal cortex, where the sense of smell resides, and loss of the sense of smell is one of the earliest potential signs of Alzheimer’s.
Developing effective therapies for CTE and other neurodegenerative diseases involving tau is hampered in part because little is currently understood about what levels and distribution of tau prion aggregation correspond to symptom onset, types of symptoms, and their progression. While techniques for imaging tau progression in the human brain remain elusive, doing so in the CTE animal model would reveal these correlations and provide the basis for testing experimental therapies in the animal model and thereafter in human CTE. A CTE animal model in which tau alone can be imaged over time provides several advantages. First, scientists could visualize the actual transformation of tau proteins into prions. Doing so in the other tauopathies, where onset is uncertain, would be far more difficult. Second, CTE is a relatively rapid prion disease process, and therefore has the potential to more rapidly accelerate translation of the animal model research to human CTE studies.
To develop the model, the investigators will create “transgenic” mice with both human tau, and a “bioluminescent” imaging reporter that is regulated by the formation of tau prions. This bioluminescent reporter uses the light-emitting chemical in fireflies, so the tau prions would literally light up. The investigators then would be able to visualize the conversion of normal tau proteins into prions in live mice, and follow their spread through the brain. Successfully creating the animal model would then lead to the planned phase II research to quantify tau prion aggregation levels and distribution patterns in the brain and correlate these with the onset of various symptoms and disease progression in the animals. These findings then would provide the opportunity to test the effectiveness of various experimental therapies. Those showing promise would be candidates for human testing in CTE patients.
The model: What makes the planned CTE transgenic animal model so important in studying tau protein conversion to prions and consequent disease progression? Several factors: 1) the CTE disease process is more uniform than occurs in other tauopathies; 2) tau prion conversion can occur more rapidly from repetitive head injury than from slow disease process such as Alzheimer’s; and 3) genetically engineered bioluminescent molecular imaging of tau facilitates repeated imaging of each animal over time to reveal disease processes and progression correlated with symptoms.
What makes creating the animal model challenging? Developing two techniques: demonstrating that the bioluminescent reporter is specific for the formation of tau prions; and, inducing closed head trauma. The investigators will assess multiple approaches to inducing closed head trauma in the mouse model, beginning with indirect methods for producing a pressure wave from a blast, compressed air or sound.
Significance: Given the increasing numbers of people identified with devastating CTE, Alzheimer’s and other neurodegenerative diseases involving tau, acceleration of treatment research is an urgent priority.
Stanley B. Prusiner, M.D.
Stanley B. Prusiner, M.D., is Director of the Institute for Neurodegenerative Diseases and Professor of Neurology at the University of California, San Francisco (UCSF). He received his undergraduate and medical school training at the University of Pennsylvania and his postgraduate clinical training at UCSF.Dr. Prusiner discovered an unprecedented class of pathogens that he named prions. Prions are infectious proteins that cause neurodegenerative diseases in animals and humans. Dr. Prusiner discovered a novel disease paradigm when he showed prions cause disorders such as Creutzfeldt-Jakob disease (CJD) in humans that manifest as (1) sporadic, (2) inherited and (3) infectious illnesses. Dr. Prusiner demonstrated that prions are formed when a normal, benign cellular protein acquires an altered shape. His concept of infectious proteins as well as his proposal of multiple biologically active shapes or conformations for a single protein were considered heretical. Remarkably, the more common neurodegenerative diseases including Alzheimer’s, Parkinson’s and many of the frontotemporal dementias as well as some forms of ALS have been shown to be caused by prions over the past five years. Prusiner predicted a prion etiology for these common degenerative diseases based on his seminal discovery that prions can assemble into amyloid fibrils. Much of Dr. Prusiner’s current research focuses on developing therapeutics aimed at halting neurodegeneration in Alzheimer’s, Parkinson’s, the frontotemporal dementias and Creutzfeldt-Jakob disease.Dr. Prusiner is a member of the National Academy of Sciences, the Institute of Medicine, the American Academy of Arts and Sciences and the American Philosophical Society, and a foreign member of the Royal Society, London. He is the recipient of numerous prizes, including the Potamkin Prize for Alzheimer’s Disease Research from the American Academy of Neurology (1991); the Gairdner Foundation International Award (1993); the Albert Lasker Award for Basic Medical Research (1994); the Nobel Prize in Physiology or Medicine (1997); and the United States National Medal of Science (2009).