URMC-099 facilitates amyloid-β clearance in a murine model of Alzheimer's disease

Background: The mixed lineage kinase type 3 inhibitor URMC-099 facilitates amyloid-beta (A beta) clearance and degradation in cultured murine microglia. One putative mechanism is an effect of URMC-099 on A beta uptake and degradation. As URMC-099 promotes endolysosomal protein trafficking and reduces A beta microglial pro-inflammatory activities, we assessed whether these responses affect A beta pathobiogenesis. To this end, URMC-099's therapeutic potential, in A beta precursor protein/presenilin-1 (APP/PS1) double-transgenic mice, was investigated in this model of Alzheimer's disease (AD). Methods: Four-month-old APP/PS1 mice were administered intraperitoneal URMC-099 injections at 10 mg/kg daily for 3 weeks. Brain tissues were examined by biochemical, molecular and immunohistochemical tests. Results: URMC-099 inhibited mitogen-activated protein kinase 3/4-mediated activation and attenuated beta-amyloidosis. Microglial nitric oxide synthase-2 and arginase-1 were co-localized with lysosomal-associated membrane protein 1 (Lamp1) and A beta. Importatly, URMC-099 restored synaptic integrity and hippocampal neurogenesis in APP/PS1 mice. Conclusions: URMC-099 facilitates A beta clearance in the brain of APP/PS1 mice. The multifaceted immune modulatory and neuroprotective roles of URMC-099 make it an attractive candidate for ameliorating the course of AD. This is buttressed by removal of pathologic A beta species and restoration of the brain's microenvironment during disease.