P3‐432: an Inhibitor of Kynurenine 3‐monooxygenase is Neuroprotective in a Mouse Model of Alzheimer's Disease

Kynurenine 3-monooxygenase (KMO) is an enzyme in the kynurenine pathway for tryptophan degradation that has been hypothesized to play an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. Objective: To determine if KMO modulates pathophysiology in a mouse model of AD. We analyzed the effects of oral administration of JM6, a novel small molecule inhibitor of KMO, on behavioral and neuropathological deficits in a well-established mouse model of AD. JM6 completely rescued anxiolytic behavior and spatial memory deficits in transgenic mice that express human amyloid precursor protein (hAPP) with familial AD (FAD) mutations. JM6 ameliorated the loss of the pre-synaptic protein synaptophysin in the hippocampus and cortex of hAPPFAD mice in a highly significant manner, and also increased levels of c-Fos, a marker for neuronal activity in the granular layer of the dentate gyrus. These effects may be attributed to a JM6-induced decrease of KMO activity and subsequent increases in kynurenic acid levels in the serum and brains of hAPPFAD mice. These findings provide the first in vivo evidence that modulation of the kynurenine pathway improves pathophysiology and behavior in a mouse model of AD and implicate KMO as a disease-modifying enzyme in this disease. As KMO is expressed predominantly in immune cells, these results contribute to evidence that the immune system may play an important role in AD. More importantly, JM6, or related KMO inhibitors, may ultimately facilitate testing of the clinical relevance of the kynurenine pathway in AD patients.