ERAD-STING Crosstalk in Microglia: Unraveling the Pathogenesis of Alzheimer's Disease ABSTRACT Alzheimer’s disease (AD) is an age-dependent progressive neurodegenerative disease and the most common form of dementia. Although amyloid- and Tau-mediated proteinopathies are the proposed main drivers, emerging evidence from both patients and animal models have clearly indicated that the disease is much more complicated at genetic, molecular and cellular levels. In responding to PAR-22-093, we propose to explore the role of innate immunity and its new regulatory mechanism in neuroinflammation associated with AD. The MPI team, composed of the Qi (UVA) and Zhao (USC) laboratories, will investigate the role of STING and its crosstalk with protein quality-control mechanism known as endoplasmic reticulum (ER)-associated degradation (ERAD) in AD pathogenesis. The Qi laboratory has been exploring the physiological role of SEL1L-HRD1 ERAD complex, a principal mechanism for the recruitment and retro-translocation of misfolded ER proteins for cytosolic proteasomal degradation for the last 15 years, While the Zhao laboratory has been focused on the role of innate immunity in neurodegeneration and AD pathogenesis for the past decade. We recently reported independently that STING is controlled by ERAD at the ER of macrophages (Qi Nat Cell Biol 2023), and that STING activation in microglia is a major driving force of neuroinflammation and AD pathogenesis (Zhao Nat Aging 2023). Recently, the two teams collaboratively generated strong preliminary data providing further support for the importance of the ERAD-STING axis in amyloid AD pathologies. Our central hypothesis proposes that chronic activation of STING-mediated innate immunity in the brain is a fundamental mechanism underlying neuroinflammation in AD pathogenesis, which is regulated by SEL1L-HRD1 ERAD. This study establishes the pivotal role of innate immunity and its crosstalk with the ER quality control mechanism in AD progression. We will delineate how this new axis influence the amyloid metabolism, neuroinflammation and AD pathogenesis in the following aims: (1) Determine the functions of cGAS-STING on amyloid metabolism and neurodegeneration; (2) Delineate the importance of ERAD-STING crosstalk in AD pathogenesis; and (3) Define the cellular mechanism for ERAD-STING-mediated neurodegeneration in AD. Hence, this MPI team with complementary expertise in cell biology/immunology and neuro-/AD-biology will establish the cGAS-STING pathway as a critical molecular link between innate immunity and AD, and uncover the importance of SEL1L- HRD1 ERAD as a novel regulator of STING-mediated neuroinflammation in aging and AD. HUMAN RELEVANCE: A better understanding of this innate immune pathway in CNS inflammation and its regulatory mechanism will help unveil the complex etiology and heterogeneity in AD, provide novel insights into novel therapeutic targets for AD and identify potential drug designs targeting the STING i...