Koster Kevin P, Smith Conor, Valencia-Olvera Ana C, Thatcher Gregory R J, Tai Leon M, LaDu Mary Jo
Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, United States.
Curr Top Med Chem. 2017;17(6):708-720. doi: 10.2174/1568026616666160617090227.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by amyloid plaques, composed of amyloid-beta peptide (Aβ) and neurofibrillary tangles, composed of aberrantly phosphorylated tau. APOE4 is the greatest genetic risk factor for AD, increasing risk up to 12- fold with a double allele compared to APOE3. In contrast, APOE2 reduces AD risk ~2-fold per allele. Accumulating evidence demonstrates that apolipoprotein E4 (apoE4) plays a multifactorial role in AD pathogenesis, although the exact mechanisms remain unclear. Further data support roles for apoE4 as a toxic gain of function or loss of positive function in AD, a discrepancy that has significant implications for the future of apoE-directed therapeutics. However, recent evidence repurposing retinoid X receptor (RXR) agonists, or rexinoids, for the treatment of AD demonstrates conflicting, though potentially beneficial effects in familial AD-transgenic (FAD-Tg) mouse models. Of particular note is bexarotene (Targretin®), a selective rexinoid previously utilized in cancer treatment emerging as a viable candidate for AD clinical trials. However, the mechanism of action of bexarotene and similar rexinoids remains controversial, particularly in the context of human APOE. In addition, rexinoids demonstrate distinct adverse event profiles in humans that may have greater detrimental effects in an elderly AD population. Therefore, this special issue review discusses the implications for rexinoiddirected therapeutic strategies in AD, the potential mechanistic targets, and future directions for the improvement of rexinoid-based therapies in AD.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征为淀粉样斑块（由β淀粉样肽（Aβ）组成）和神经原纤维缠结（由异常磷酸化的tau组成）。APOE4是AD最大的遗传风险因素，与APOE3相比，双等位基因可使风险增加高达12倍。相比之下，APOE2每个等位基因可使AD风险降低约2倍。越来越多的证据表明，载脂蛋白E4（apoE4）在AD发病机制中发挥多方面作用，但其确切机制仍不清楚。更多数据支持apoE4在AD中作为功能毒性获得或正功能丧失的作用，这种差异对apoE导向治疗的未来具有重要意义。然而，最近将视黄酸X受体（RXR）激动剂或类视黄醇重新用于AD治疗的证据表明，在家族性AD转基因（FAD-Tg）小鼠模型中，其效果相互矛盾但可能有益。特别值得注意的是贝沙罗汀（Targretin®），一种先前用于癌症治疗的选择性类视黄醇，正成为AD临床试验的可行候选药物。然而，贝沙罗汀和类似类视黄醇的作用机制仍存在争议，尤其是在人类APOE的背景下。此外，类视黄醇在人类中表现出不同的不良事件特征，这可能对老年AD患者群体产生更大的有害影响。因此，本期专题综述讨论了类视黄醇导向治疗策略在AD中的意义、潜在的作用机制靶点以及改善基于类视黄醇的AD治疗的未来方向。
