The Impact of PERK on Posttraumatic Tauopathy in Alzheimer s Disease
Abstract
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 reticulum (ER) stress is one of the most notable and long-lasting cascades that are activated by injury. ER stress activates a protein called PERK, which is responsible for initiating protective cascades that help restore ER function. 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 aggregation 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 TBI causes activation of PERK. To accomplish this objective, mice will be subjected to TBI 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 a TBI. 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. If successful, this grant will not only identify a molecular mechanism that links injury and AD, but 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.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510551
Entities
People
- Jose F Abisambra
Organizations
- United States Army
- University of Kentucky