Mitochondrial Dysfunction and Oxidative Stress Effect on Tau Pathology Using Chemo/Optogenetics

PROJECT ABSTRACT Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that results in neuronal cell death. AD pathology involves protein aggregation, with tau protein being a primary driver of the disease. However, the mechanisms that initiate aggregation and pathological tau accumulation remains unclear. Neurons are energetically demanding cells. Mitochondria are central in maintaining their ATP levels and AD models have decreased ATP production. Thus, mitochondrial dysfunction is a hallmark of AD. Damaged and dysfunctional mitochondria lead to decreased energy and elevated reactive oxygen species (ROS) production, which can severely impact neuronal health. Interestingly, mitochondrial dysfunction has been linked to promoting and even preceding tau pathology in AD. Tauopathy mouse models, such as the P301S tau mice, present with mitochondria dysfunction and increased ROS prior to pathological tau accumulation. Additionally, mice lacking superoxide dismutase (SOD), an essential antioxidant enzyme, had increased pathological tau that was alleviated by treatment with exogenous antioxidants. These studies, and others, suggest there is a direct relationship between tau pathology and mitochondria. However, mitochondrial function and ROS production are difficult to isolate experimentally, so it is unclear what the effect of each is on tau pathology. Therefore, in this proposal, we will be utilizing approaches that have spatial and temporal control to target mitochondrial function and ROS production and determine the effect on tau pathology. In Aim 1, we will use chemo- and optogenetics to examine the role of ROS production in initiating tau pathology. With our approaches, ROS will be localized to specific cellular compartments and generated at different levels. The ability to control the amount and type of ROS will allow us to categorize ROS into two types: signaling and damaging. We will assess the effect on tau pathology, with preliminary data suggesting ROS signaling increases the levels of pathological tau. In Aim 2, we will target a light-activated proton pump to the mitochondria P301S tau neurons. The goal of this aim is to recover the mitochondrial function with the activation of the proton pump, as P301S tau mice have been demonstrated to have reduced energy production early on in their development. Thus, improving the mitochondrial function may alleviate the accumulation of pathological tau species in the P301S tau neurons. For both of the aims, we will use both in vitro primary neurons and ex vivo organotypic brain slices from mice. The experiments that I have proposed are readily achievable and will advance the field in identifying mechanisms involved in tau pathology and, ultimately, AD progression.