Mitochondrial dysfunction and tau pathology in Alzheimer's disease

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Alzheimer’s disease (AD) is the most common cause of dementia with no current interventions that halt or substantially slow disease progression. AD is a multifactorial disease characterized by impaired mitochondrial bioenergetics, oxidative stress, and tau pathology. These AD pathologies are interconnected, change over time, and correlate with neuronal dysfunction. Moreover, the hallmarks are dynamic and difficult to isolate experimentally, which makes assigning causation challenging and limits therapeutic development. This proposal uses novel optogenetic technology developed for hypoxic biology to address this gap and test if mitochondrial dysfunction and reactive oxygen species (ROS) production are causal for the progression of tau pathology. Our approach involves directly controlling mitochondrial function and ROS production using light, without interfering with metabolism or using irreversible toxins with off-target effects. The optogenetic tools mitochondria-ON (mtON) and mitochondria-OFF (mtOFF) are mitochondria-targeted light-activated proton pumps that alter mitochondrial bioenergetics to turn ‘on’ or ‘off’ mitochondrial function in response to light. Similarly, mtSuperNova is a mitochondria-targeted genetically-encoded photosensitizer which generates ROS in response to light. These tools will spatiotemporally control mitochondrial function and ROS production in both an ex vivo brain slice culture and an in vivo mouse model using the PS19 mouse line (P301S tau). These mice exhibit early mitochondrial dysfunction and have been used extensively to study tau pathology and are an optimal model for these studies. Organotypic brain slice cultures will be used to provide a three-dimensional system to mechanistically test when and how mitochondrial energetics and ROS production contribute to pathological tau modifications. AD is largely associated with aging; therefore, in we will bridge our ex vivo findings into an adult in vivo model. Using a wireless optogenetic system, we will illuminate hippocampi in live, freely moving PS19 adult mice to test the effect of mitochondrial dysfunction over time on measures of oxidative stress and tau pathology. Mitochondrial dysfunction and ROS production have long been associated with AD pathology however the cause-and-effect relationship is unclear. Our novel technology provides an approach to directly test the role of mitochondria in AD independent of confounding factors. Overall, these studies will begin to clearly define the role of mitochondria in the evolution of tau pathology and provide mechanistic insights into therapeutic opportunities to attenuate AD pathogenesis.