Epac1 Signaling Promotes Retinal Neuronal Injury During Tauopathy

Epac1 Signaling Promotes Retinal Neuronal Injury During Tauopathy SUMMARY Tauopathies, characterized by abnormal neurofibrillary tangle formation of aggregated and/or hyper- phosphorylated tau and neurotoxicity, is a hallmark of Alzheimer's disease (AD) and a number of other neurodegenerative disorders. Tauopathies are among the most crippling conditions that affect our rapidly growing aging population. Due to the lack of effective diagnostics and treatments, these diseases significantly impair patient's health and impose major financial burdens to patients, their families and the society. The retina is an extension of the neural network of the brain. Accumulating pre-clinical and clinical studies have revealed a strong link between AD and retinal dysfunctions such as amyloid beta (Aβ) deposit, tau phosphorylation and aggregation, and retinal nerve fiber layer thinning. Our recent studies have demonstrated that retinas underwent alterations in the neurovascular unit that precede brain pathology in a mouse model of tauopathy. These results suggest that the retina undergoes pathological changes during tauopathy. Yet, its underlying mechanisms remain unclear. In addition, visual impairment is prevalent in AD patients and a major concern since it significantly affects the quality of life of AD patients and contributes to cognitive decline. However, few studies have been conducted to address this problem. A better understanding of the mechanisms of vision loss in tauopathy and the development of new strategies to treat or prevent vision impairment will address an urgent unmet medical need. In this application, we will test the hypothesis that activation of the cAMP/Epac1 pathway is a novel mechanism of retinal neurodegeneration during tauopathy by inducing mitochondrial dysfunction, promoting tau SUMOylation and phosphorylation, and reducing the clearance of tau aggregates and damaged mitochondria, therefore represents a new therapeutic target for vision impairment during tauopathy. We will employ a multidisciplinary experimental strategy to uncover the significance of Epac cascade in retinal neuronal injury during tauopathy, define its underlying mechanisms, and explore therapeutic potential of a class of newly developed and optimized Epac-specific inhibitors for suppressing tauopathy and preventing retinal neuronal dysfunction and degeneration. This proposal is highly in line with the following studies of interest highlighted in “NOT-AG-21-044”: “Studies that aim to understand the etiology of sensory and motor dysfunctions in preclinical AD”. Completion of the proposed studies will provide important new knowledge that will fill the current knowledge gaps and provide scientific base for preventing and treating retinal neurodegeneration during tauopathies including AD. Project Number: 1R01AG091781-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Wenbo Zhang (+1 co-PI) | Institution: UNIVERSITY OF TEXAS MED BR GALVESTON, GALVESTON, TX | Award Amount: $617,349 | Activity Code: R01 | Study Section: Pathophysiology of Eye Disease - 1 Study Section[PED1] View on NIH RePORTER: https://reporter.nih.gov/project-details/11237795