OAB-14, a bexarotene derivative, improves Alzheimer's disease-related pathologies and cognitive impairments by increasing β-amyloid clearance in APP/PS1 mice

The pathogenesis of Alzheimer's disease (AD) is complex, though the clinical failures of anti-AD candidates targeting A beta production (such as beta- and gamma-secretase inhibitors) make people suspect the Al3 hypothesis, in which the neurotoxicity of A beta is undoubtedly involved. According to studies, > 95% of AD patients with sporadic AD are primarily associated with abnormal A beta clearance. Therefore, drugs that increase A beta clearance are becoming new prospects for the treatment of AD. Here, the novel small molecule OAB-14, designed using bexarotene as the lead compound, significantly alleviated cognitive impairments in amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice after administration for 15 days or 3 months. OAB-14 rapidly cleared 71% of A beta by promoting microglia phagocytosis and increasing IDE and NEP expression. This compound also attenuated the downstream pathological events of A beta accumulation, such as synaptic degeneration, neuronal loss, tau hyperphosphorylation and neuroinflammation in APP/PS1 mice. Moreover, OAB-14 had no significant effect on body weight or liver toxicity after acute and chronic treatment. OAB-14 was well tolerated and its maximum-tolerated dose in mice was > 4.0 g/kg. Based on these findings, OAB-14 represents a promising new candidate for AD treatment.