The impact of PERK on post-traumatic tauopathy in Alzheimers disease

This study will establish for the first time the molecular mechanism linking traumatic brain injury (TBI) and onset of tau pathology that is associated with Alzheimer’s disease (AD). Our preliminary data suggest that endoplasmic reticu-lum stress is one of the most notable and long-lasting cascades that are activat-ed by injury. In addition, we recently identified that the ER stress sensor PERK induces tau to adopt toxic conformations that are associated with disease. There-fore, the overall hypothesis of this project is that TBI induces long-lasting activa-tion 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 three aims. In Aim 1, mice will undergo a TBI event and different intensities (control, mild, moderate, and severe), and PERK levels will be measured over time (1d, 7d, 30d, and 90d). PERK levels will be measured using immunohistochemical (IHC) In Aim 2, PERK will be activated in tau transgenic and non-transgenic control mice using a chem-ical compound or a TBI event (moderate and severe). Similarly, we will use IHC and MSD/WB to measure changes in the levels of proteins such as PERK, active PERK, and pathological tau species. Finally, in Aim 3, we will use a genetic and a chemical mechanism to inhibit PERK in tau transgenic mice. Genetically, we will cross tau transgenic mice with a transgenic mouse that lacks an allele coding for PERK. Chemically, we will treat tau transgenic mice with a PERK inhibitor. The proposed outcome measures are manganese-enhanced MRI, electrophysio-logical testing, MSD/WB, cognitive testing, and IHC. 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 inhibi-tors 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.