Alzheimer’s disease (AD), the most common form of late-onset dementia in the elderly, poses an existential threat to our health care system in modern society. It is characterized by the accumulation of pathological amyloid beta (Aβ) plaques and neurofibrillary tangles. There is compelling evidence from postmortem studies of both aging and AD showing that tau pathology rather than Aβ pathology more closely relates to memory decline. Most therapeutic strategies have focused on anti-Aβ approaches that largely have failed. More recent tau imaging studies provide further evidence that tau imaging, not Aβ imaging, shows a strong regional association with clinical and anatomical heterogeneity in AD. Understanding pathogenic mechanisms that cause dysfunction in tauopathies is urgently needed to identify novel therapeutic targets to treat AD. Moreover, effective lead inhibitors and chemical tools are required to validate whether such targets are appropriate for pharmacological intervention. This proposal focuses on identification and development of potent inhibitors of a DNA-sensing enzyme, cGAS, which sits at the top of the inflammatory pathway that is also observed in AD and is recapitulated in the tauopathy mouse model of AD. Here, we will perform virtual high-throughput screening (vHTS) to identify hit cGAS inhibitors and evaluate the identified hit compounds to obtain highly potent inhibitors of human cGAS as tool compounds. The latter subsequently can be developed as lead inhibitors for treatment of AD.