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

Publication date: Available online 30 October 2018Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Chunling Yuan, Xiaoli Guo, Qifan Zhou, Fangyu Du, Wei Jiang, Xiaoyu Zhou, Peng Liu, Tianyan Chi, Xuefei Ji, Jinheng Gao, Chengwen Chen, Hongli Lang, Jia Xu, Danyang Liu, Yang Yang, Shimeng Qiu, Xing Tang, Guoliang Chen, Libo ZouAbstractThe 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 a...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research