UC San Diego

The dissertation addresses the imperative need to understand the molecular mechanisms underlying Alzheimer’s disease (AD), traumatic brain injury (TBI), and other neurological disorders. AD, a prevalent neurodegenerative disease, and TBI, a significant risk factor for AD, impose severe cognitive deficits and memory loss, emphasizing the urgency for advancing our comprehension of their pathogenic mechanisms. Cytosolic cathepsin B has been implicated in cell death and neuroinflammation in AD and TBI, making it a potential therapeutic target. Pathogenic, cytosolic cathepsin B in disease conditions results from lysosomal leakage of cathepsin B to the cytosol. Research has shown elevated levels of cathepsin B in various neurological disorders, including AD and TBI, highlighting its involvement in disease pathology. Notably, cathepsin B displays distinct cleavage properties at lysosomal acidic pH 4.6 and cytosolic neutral pH 7.2, suggesting its dynamic role in different cellular compartments. To investigate this further, pH-selective inhibitors, such as Z-Arg-Lys-AOMK and CA-074, were developed to target cathepsin B in specific pH environments. Additionally, a novel fluorescent substrate, Z-Nle-Lys-Arg-AMC, was designed to monitor cathepsin B activity across a wide pH range with high specificity. Utilizing these tools, the study aims to assess the role of cytosolic cathepsin B in cell death in mouse microglia BV2 cells and TBI mouse models. Experimental studies in a mouse model of traumatic brain injury (TBI) show that injury increases cytosolic cathepsin B associated with motor behavioral deficits, modulated by the neutral pH selective inhibitor of cathepsin B, Z-Arg-Lys-AOMK. Treatment of TBI mice with Z-Arg-Lys-AOMK improved neuromotor function, and inhibited TBI-induced cytosolic cathepsin B. Further in vivo investigation of the role of cytosolic cathepsin B in behavioral deficits and neuropathology in animal models of neurological diseases are needed to evaluate the therapeutic potential of targeting cathepsin B in particular brain disorders. In conclusion, this dissertation sheds light on the complex role of cathepsin B in neurological disorders and offers novel insights into its therapeutic targeting. By elucidating the molecular mechanisms underlying AD, and TBI, this research paves the way for the development of innovative treatments for future therapeutic interventions in neurological disorders.