Abstract
The pathogenesis of Alzheimer's disease (AD) is complex, though the clinical failures of anti-AD candidates targeting Aβ production (such as β- and γ-secretase inhibitors) make people suspect the Aβ hypothesis, in which the neurotoxicity of Aβ is undoubtedly involved. According to studies, >95% of AD patients with sporadic AD are primarily associated with abnormal Aβ clearance. Therefore, drugs that increase Aβ 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 Aβ by promoting microglia phagocytosis and increasing IDE and NEP expression. This compound also attenuated the downstream pathological events of Aβ 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.