Abstract Alzheimer’s disease (AD) affects an estimated 5.7 million Americans, a number expected to reach 14 million by 2050. Despite several decades of research, the initiation and progression of AD continues to be poorly understood, indicating the need for novel therapeutic strategies. There is mounting evidence that neuroinflammation plays an important role in the progression of AD. We are proposing to investigate Cmpd 10357, a novel UCD small molecule originally developed as a highly selective anti-cancer agent, for treatment of AD. Cmpd 10357 selectively targets intracellular protein complexes containing the serine protease inhibitor, plasminogen activator inhibitor-1 (PAI-1). PAI-1 functions as the primary inhibitor of tissue plasminogen activator (tPA) and urokinase (uPA). PAI-1 is not expressed in the normal brain, but its expression is markedly increased in cytokine-activated microglia and astrocytes, and increased PAI-1 expression has been demonstrated in AD patients and AD animal models. High levels of PAI-1 expression and secretion by activated microglia and astrocytes inhibits plasmin activation by serine proteases and has been demonstrated to decrease Aβ protein degradation, thereby promoting plaque formation. We hypothesize that Cmpd 10357 will selectively target and kill activated microglia and astrocytes in the AD brain that express PAI-1, thereby slowing or preventing progression of AD via potentially two mechanisms: (i) reducing neuroinflammation; and/or (ii) improving Aβ clearance from the brain. To test this hypothesis, we will investigate the drug’s impact on neuroinflammatory status, AD pathology, and cognitive dysfunction in the transgenic TgF344-AD rat model. The objectives are to determine whether weekly intraperitoneal administration of Cmpd 10357 attenuates neuroinflammatory changes and plaque formation in the TgF344-AD rat and assess the impacts of these changes on the progression of AD pathology and cognitive decline. This project leverages an ongoing collaboration between the PIs that has resulted in publications characterizing the anti-inflammatory properties and novel drug mechanisms of action of two new classes of small molecules. Consistent with the goals of the R21 funding mechanism, this project is high risk, but if successful, high payoff in that it will generate proof-of- concept data for a novel therapeutic candidate for AD that potentially works via both Aβ-independent and dependent mechanisms. Findings from these studies may also validate Cmpd 10357 as a potential therapeutic approach for other neurological diseases with a predominant neuroinflammatory component, as well as a tool compound for addressing the controversy regarding the neuroprotective vs. neurotoxic role of microglia and astrocytes in AD by enabling the selective death of PA1-expressing glia at specific stages in the progression of AD in preclinical models.