325 Tyrosine kinase inhibition reduces pathological markers of Alzheimer’s Disease

Abstract

OBJECTIVES/GOALS: Alzheimer’s Disease (AD) displays numerous pathological features, including amyloid-beta deposition, extensive neuroinflammation, and vascular fibrosis. However, putative therapeutic options for alleviating these features remain limited, emphasizing the need to develop comprehensive treatments for patients with AD. METHODS/STUDY POPULATION: CSF from human AD patients treated with nilotinib (n=12), a tyrosine kinase inhibitor, or placebo (n=11) was collected and sequenced, and significantly altered miRNAs were identified and analyzed for alterations to disease-associated genes via gene ontology analysis. TgAPP mice were injected intraperitoneally with one of two novel tyrosine kinase inhibitors, BK40143 or BK40197, or DMSO (n=12 per group) daily for six weeks, during which memory deficits between groups were measured, before brains were harvested for analysis of amyloid-beta load via ELISA, microglial activation via Sholl analysis, and vascular collagen levels via immunohistochemistry. RESULTS/ANTICIPATED RESULTS: CSF obtained from AD subjects treated with nilotinib revealed significantly increased (p<0.05) levels of miRNAs regulating autophagy, neuroinflammation, and collagen production compared to placebo. These results were validated in vivoin TgAPP mice, who displayed improved recall on the novel object recognition test and Morris water maze following treatment with our drugs, correlating with decreased levels of brain amyloid-beta (30% decrease, p=0.002), decreased microglial reactivity and activation (40% decrease, p=0.01), and decreased vascular fibrosis (50% decrease, p=0.005) along small brain blood vessels compared to controls. DISCUSSION/SIGNIFICANCE: These data identify tyrosine kinase inhibition as a valid therapeutic strategy for alleviating various pathological features associated with AD and warrant further investigation as a treatment option for human patients as a means of slowing cognitive decline.