SEN1500, a novel oral amyloid-β aggregation inhibitor, attenuates brain pathology in a mouse model of Alzheimer's disease

Introduction: Amyloid-p (All) aggregation is thought to be a major pathogenic event underlying the neuropathology of Alzheimer's disease (AD). The development of new drugs inhibiting the A beta aggregation process is, therefore, important. SEN1500, an orally bioavailable and CNS-penetrant A beta aggregation inhibitor, has previously been shown to reduce spatial learning and memory deficits in an APP transgenic mouse model. To verify that the pharmacological properties of SEN1500 are not unique to this model, we investigated brain A beta pathology, neuroinflammation, as well as memory in a different mouse model of AD expressing the human amyloid precursor protein with Swedish and London mutations (APP(SL)). Materials & methods: APP(SL) transgenic mice and non-transgenic littermates were treated with SEN1500 via food pellets from three months of age for four months. At the end of the treatment, animals were tested for memory deficits using the contextual fear conditioning test and brain tissue was analyzed for soluble and insoluble amyloid-beta 1-38, -40, -42, beta-amyloid plaques, beta-sheet plaque cores, as well as for astrocytosis and activated microglia. Results: SEN1500 treatment lowered insoluble AD levels and beta-amyloid plaque load in the brain compared with control-treated APP(SL) mice. Activated microglia were significantly reduced in the cortex but not the hippo campus of SEN1500-treated APP(SL) mice. Memory deficits of APPSL mice could not be rescued by SEN1500. Discussion: SEN1500 is not only able to reduce A beta pathology and activated microglia but also to improve learning and memory as previously shown, making SEN1500 a potential candidate for human AD treatment. This A beta aggregation inhibitor could be a promising therapeutic agent for the disease-modifying treatment of AD.