This study will establish the molecular mechanism linking mild repetitive traumatic brain injury (mrTBI) and onset of tau pathology that is associated with Alzheimer's disease (AD). Our preliminary data suggest that endoplasmic reticulum stress is a notable and long-lasting cascade that is activated by injury. ER stress acti- vates a protein called PERK, which is responsible for initiating protective pathways that help restore ER func- tion. However, long-term activation of PERK leads to cell death. Brain cells are particularly susceptible to PERK-mediated cell death. Indeed, a common sign between TBI and AD is PERK hyperactivity. We recently established that another common pathological hallmark of TBI and AD, abnormal aggrega- tion of the protein tau, is driven by chronic activation of PERK. PERK induces tau to adopt toxic conformations that are associated with disease. Therefore, the overall hypothesis of this project is that TBI induces long- lasting activation of PERK, which in turn catalyzes the formation of pathological tau species. This ultimately leads to increased risk for AD. We will test our hypotheses using mouse models in two aims.
In Aim 1, we will determine the conditions under which mrTBI causes activation of PERK. To accomplish this objective, mice will be subjected to mrTBI at different intensities and for different time points, and the levels of active PERK will be measured. In addition, we will determine the extent of tissue that shows PERK activity.
In Aim 2, we will manipulate PERK activity in mouse models of tauopathy that have suffered mrTBI. We expect that PERK activation will cause more tau pathology and induce damage to brain function. Conversely, PERK inhibition will restore brain function and prevent tau pathology.
Aim 3 will determine the validity of using PERK as a biomarker of TBI. Our preliminary data suggest that individuals who suffered one or more TBIs in their lifetime have two times more active/total PERK ratio in their blood. These data support our enthusiasm to expand our studies into a much larger cohort. If successful, this grant will not only identify a molecular mechanism that links injury and AD, but it will also highlight a key pathological pathway replete with therapeutic targets. Logical extensions of these studies involve testing inhibitors of the PERK pathway for potential therapeutic value. It will also offer relief to the 1.7 million people in the United States who suffer a TBI annually. Our expertise in ER stress, PERK, tau, AD, and TBI makes us uniquely suited to accomplish the pro- posed work. In addition, the unique resources available to my lab, such as small animal MR imaging, ADC co- hort biospecimens and clinical histories, and the COBRE Viral Production Core have strengthened the impact of our work and brought us closer to understanding the mechanisms of tau-mediated neurotoxic events stem- ming from the ER. My current partnership with the Lexington VAMC, including access to serum from veterans and unique instruments for imaging and proteomics, makes our lab ideally suited to accomplish the proposed work in this application. Furthermore, despite the brief development of my research program, we have been extremely productive (27 publications since 2010 and $3.1M total funding since 2013). These achievements increase the security that I will successfully complete the proposed work. !
According to the Armed Forces Health Surveillance Center, 313,813 military personnel suffered a TBI event since deployment to Afghanistan and Iraq. Another 100,000 military personnel have undiagnosed exposure to TBI. Therefore, almost half a million military personnel have been exposed to TBI in the last 16 years. TBI is a major contributor to long-term neurologic impairments including Alzheimer's disease (AD). The sudden increase in TBI veterans, accompanied by the lack of a cure for AD, indicates that the number of AD patients will increase over the next 40-50yrs. AD is the most crippling cognitive threat to our aging population. By 2050, it is expected that the USA will spend $1.2 trillion to maintain the deteriorating quality of life of 16 million Americans with AD. As a result, there is an urgent need to identify the molecular mechanisms that drive TBI- mediated risk for AD in order to find therapeutic targets. Our research proposal directly addresses this need by testing the extent to which the PERK pathway mediates tau-induced neurodegeneration that is initiated by TBI.