Alzheimer's disease (AD) is the most common cause of dementia and one of the leading causes of death worldwide. The current failure in AD therapeutic development demands the discovery of new therapeutically actionable mechanisms underlying the disease. To address this unmet medical need, we propose to define the protein-protein interaction between p38 and MK2 as a highly promising target to control neuroinflammation, one of the major hallmarks of Alzheimer’s disease. The protein-protein interaction between mitogen-activated protein kinase p38 and its main substrate MK2 plays a central role in pro-inflammatory signaling. Both proteins are well- defined targets for therapeutic discovery, and multiple inhibitors have been proposed to control neuroinflammation by inhibiting p38 or MK2 kinase activity. However, none of the proposed inhibitors have reached the approval as a drug. The commonly recognized reasons for such failure include multiple adverse side effects associated with i) network effects of p38 inhibition on multiple p38-regulated proteins besides MK2 and ii) limited compound selectivity against other kinases. Thus, targeting p38 and MK2 individually cannot provide an efficient strategy to control neuroinflammation in AD. We propose to overcome this critical barrier by discovering small molecules to disrupt the protein-protein interaction between p38 and MK2 proteins rather than inhibit their kinase activity. The unique physical and chemical properties of the protein-protein interaction interface allow us to design highly specific compounds to precisely regulate the p38/MK2 complex avoiding the undesired interference with other axes of p38 signaling or other kinases. Toward this goal, we have established a robust high-throughput screening assay and a computational platform that already revealed the first small molecule and peptide-based disruptors of the p38/MK2 complex. Previously, we successfully applied our approach to discover small molecule inhibitors and stabilizers of disease-associated protein complexes of different types. We hypothesize that the inhibition of protein-protein interaction (PPI) between p38 and MK2 represents a novel promising strategy to control p38/MK2-dependent neuroinflammation in AD. To test this hypothesis, we will combine experimental high-throughput screening (HTS) with computational modeling to discover the first small molecule inhibitors of the p38/MK2 complex and demonstrate that p38/MK2 PPI inhibition can suppress pro-inflammatory signals and rescue AD phenotypes in cortical organoids. The completion of this study will establish the p38/MK2 interaction as a novel druggable target to control neuroinflammation, provide the first small molecules to regulate this pathogenic complex, and may enable new clinical strategies in Alzheimer's disease.