Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, Illinois 60612.
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, and University of Illinois at Chicago, Chicago, Illinois 60612.
J Biol Chem. 2014 Oct 31;289(44):30538-30555. doi: 10.1074/jbc.M114.600833. Epub 2014 Sep 12.
Previous data demonstrate that bexarotene (Bex), retinoid X receptor (RXR) agonist, reduces soluble and insoluble amyloid-β (Aβ) in Alzheimer disease (AD)-transgenic mice either by increasing the levels of mouse apolipoprotein E (apoE) or increasing ABCA1/ABCG1-induced apoE lipoprotein association/lipidation. However, although the mechanism of action of RXR agonists remains unclear, a major concern for their use is human (h)-APOE4, the greatest AD genetic risk factor. If APOE4 imparts a toxic gain-of-function, then increasing apoE4 may increase soluble Aβ, likely the proximal AD neurotoxin. If the APOE4 loss-of-function is lipidation of apoE4, then induction of ABCA1/ABCG1 may be beneficial. In novel EFAD-Tg mice (overexpressing h-Aβ42 with h-APOE), levels of soluble Aβ (Aβ42 and oligomeric Aβ) are highest in E4FAD hippocampus (HP) > E3FAD-HP > E4FAD cortex (CX) > E3FAD-CX, whereas levels of lipoprotein-associated/lipidated apoE have the opposite pattern (6 months). In E4FAD-HP, short-term RXR agonist treatment (Bex or LG100268; 5.75-6 months) increased ABCA1, apoE4 lipoprotein-association/lipidation, and apoE4/Aβ complex, decreased soluble Aβ, and increased PSD95. In addition, hydrogel delivery, which mimics low sustained release, was equally effective as gavage for Bex and LG100268. RXR agonists induced no beneficial effects in the E4FAD-HP in a prevention protocol (5-6 months) and actually increased soluble Aβ levels in E3FAD-CX and E4FAD-CX with the short-term protocol, possibly the result of systemic hepatomegaly. Thus, RXR agonists address the loss-of-function associated with APOE4 and exacerbated by Aβ pathology, i.e. low levels of apoE4 lipoprotein association/lipidation. Further studies are vital to address whether RXR agonists are an APOE4-specific AD therapeutic and the systemic side effects that limit translational application.
先前的数据表明，倍他罗汀（Bex）是一种视黄醇 X 受体（RXR）激动剂，它可以通过增加小鼠载脂蛋白 E（apoE）的水平或增加 ABCA1/ABCG1 诱导的 apoE 脂蛋白结合/脂化来减少阿尔茨海默病（AD）转基因小鼠中的可溶性和不溶性淀粉样β（Aβ）。然而，尽管 RXR 激动剂的作用机制尚不清楚，但人们主要关注的是人类（h）-APOE4，这是 AD 的最大遗传风险因素。如果 APOE4 赋予毒性获得性功能，那么增加 apoE4 可能会增加可溶性 Aβ，这可能是 AD 的近端神经毒素。如果 APOE4 丧失功能是 apoE4 的脂化，那么诱导 ABCA1/ABCG1 可能是有益的。在新型 EFAD-Tg 小鼠（过表达 h-Aβ42 和 h-APOE）中，可溶性 Aβ（Aβ42 和寡聚 Aβ）的水平在 E4FAD 海马（HP）> E3FAD-HP > E4FAD 皮层（CX）> E3FAD-CX 中最高，而脂蛋白结合/脂化的 apoE 水平则相反（6 个月）。在 E4FAD-HP 中，短期 RXR 激动剂治疗（Bex 或 LG100268；5.75-6 个月）增加了 ABCA1、apoE4 脂蛋白结合/脂化和 apoE4/Aβ 复合物，降低了可溶性 Aβ，并增加了 PSD95。此外，水凝胶递送（模仿低持续释放）与灌胃给药一样，对 Bex 和 LG100268 同样有效。在预防方案（5-6 个月）中，RXR 激动剂对 E4FAD-HP 没有产生有益效果，实际上在短期方案中增加了 E3FAD-CX 和 E4FAD-CX 中的可溶性 Aβ 水平，这可能是由于系统性肝肿大的结果。因此，RXR 激动剂解决了与 APOE4 相关的功能丧失问题，并因 Aβ 病理学而加剧，即 apoE4 脂蛋白结合/脂化水平较低。进一步的研究对于确定 RXR 激动剂是否是一种特定于 APOE4 的 AD 治疗方法以及限制转化应用的全身副作用至关重要。
