Probing the Influence of Oxygen Toxicity on Tau Hyperphosphorylation caused by Mitochondrial Dysfunction - Project Summary / Abstract Most mortality-causing diseases of aging, including Alzheimer’s disease and its related dementias (ADRDs), cancer, and heart disease, are exacerbated by aberrant mitochondrial function. Mitochondrial dysfunction is one of the earliest known features of ADRDs such as frontotemporal lobar degeneration (FTLD). Yet its multivariate roles in causing the molecular chain of events that lead to neurodegeneration and cognitive decline remain unknown. Increasing evidence demonstrates there is significant commonality and overlap in the pathophysiology of mitochondrial failure in aging-related disorders and mitochondrial disease using a leading mammalian model missing the electron transport chain protein NDUFS4. These mice exhibit severe neurodegeneration, weight loss, and premature death. Decreased activity of the electron transport chain, which is similarly observed in ADRD patients, is hypothesized to promote the build-up of oxygen in the brain causing oxidative damage, neuroinflammation, and neuronal cell death. Chronically housing these mitochondrial disease mice at reduced oxygen concentrations remarkably extends lifespan 10-fold, prevents loss of weight and body fat, prevents astrogliosis, microglial activation, neuroinflammation, brain lesions, and the disease phenotypes. Follow-up experiments indicate NDUFS4-KO mice have ~3-fold increases in tau phosphorylation at known pathogenic sites and hippocampal tau aggregation. Tau is a microtubule binding protein that stabilizes its assembly for proper physiology, however, excess tau phosphorylation destabilizes microtubules and forms proteotoxic aggregates that are common features of tau pathology. Housing mitochondrial disease mice in low O2 chambers prevents aberrant tau, Gsk3β, and TTBK2 phosphorylation amongst other changes. This data clearly reveals that mitochondrial dysfunction elicits tau hyperphosphorylation, and suggests aberrant O2 status may be a driving factor. Furthermore, hypoxic regimens prevent tau hyperphosphorylation and double lifespan in transgenic nematodes expressing human tau. The proposed work will provide critical insights into the mechanistic underpinnings of oxygen-induced tau hyperphosphorylation caused by mitochondrial dysfunction taking a hypothesis driven approach based on preliminary data and literature precedent. It will characterize tau pathology and illuminate the role of tau kinase Gsk3β in mitochondrial disease. It will also probe changes in interorganellar communication caused by mitochondrial dysfunction and O2-induced toxicity via NADPH oxidases. Finally, this proposal will explore the influence of mitochondrial dysfunction and oxygen toxicity in well- established mammalian tauopathies, and the capacity for low oxygen interventions to prevent the onset of tau pathology. Collectively, these complementary hypothesis-driven basic science studies will provide a better understanding of mitochondrial biology and illuminate the mechanistic role of signaling pathways in regulating tau phosphorylation in mitochondrial disease. The achievement of these aims may even have broader implications in the prevention of other diseases of normative aging such as ADRDs, heart disease, and cancer.
