Prospective Evaluation of Chloride Channel-Targeted Therapy for Alzheimer's disease

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ABSTRACT This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-AG- 22-025. As the most common form of dementia, Alzheimer's disease (AD) is one of the major causes of disability and death among older people. It causes significant economic impacts on society. The prevalence of clinical AD was 11.3% (6.1 million people in US) and this number is predicted to rise to 14 million in 2060. Therefore, therapy that manages or delays AD’s process could significantly reduce the increasing healthcare burden. However, we still lack effective interventions for AD after 40 years of R&D efforts. The FDA’s first disease-modifying, amyloid- targeted therapy, Aduhelm, reduces amyloid deposits in the patient's brain but it has not yet been shown to affect clinical outcomes such as progression of cognitive decline. It indicates that there is an urgent need to have more options for treating Alzheimer’s disease, just as we have many treatments for cancer. cGAS-STING signaling is recognized as a crucial determinant of neuropathophysiology as the elevated signal is observed in Alzheimer's disease or related dementia. However, there are currently no cGAS or STING inhibitors available in clinical stage. Work is underway to develop clinically viable inhibitors with good drug properties. In our parent award, the subcellular chloride reporters and the organellar chemotype fingerprinting techniques could help us to investigate the physiological role of organellar chloride, which is the key to the development of under-studied, chloride channel-targeted therapy. In our preliminary study, we used non- selective chloride channel blockers to induce the whole cell chloride dysregulation. We found that the non- selective chloride channel blockers inhibited the cytosolic-DNA stimulated cGAS-STING signaling in a dose- dependent manner without causing cell death. We hypothesize that cellular/organellar chloride plays an important role in the cGAS-STING signaling pathway. The elevated cGAS-STING signaling in Alzheimer's disease could be inhibited by disturbing the chloride levels via chloride channel targeting. We propose a prospective study, to evaluate the eligibility of chloride channel-targeted therapy for Alzheimer's disease via the attenuation of cGAS-STING pathway. In Aim 1, we will map the chloride homeostasis during the cGAS-STING activation and in Alzheimer's disease. Aim 2 focuses on investigating the role of chloride in cGAS-STING pathway and determine the ability of chloride channel-targeted therapy to suppress the elevated cGAS-STING pathway in Alzheimer's disease. The proposed research integrates organellar chloride imaging, chloride physiology investigation (cGAS-STING), and chloride channel-targeted therapy for Alzheimer’s disease. At the end of the proposed study, we anticipate understanding the role of cellular chloride in cGAS-STING pathway and prospectively evaluate the eligibility of chloride channel-targeted therapy to dampen the elevated cGAS- STING signaling in Alzheimer's disease. It will lay the foundation for chloride physiology and prospective validation of chloride channel-targeted therapy for Alzheimer's disease and related neurological disorders.