Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, UK.
Department of Chemistry, Durham University, Science Laboratories, South Road, Durham, UK.
J Alzheimers Dis. 2020;73(3):935-954. doi: 10.3233/JAD-190931.
Retinoic acid has been previously proposed in the treatment of Alzheimer's disease (AD). Here, five transgenic mouse models expressing AD and frontotemporal dementia risk genes (i.e., PLB2APP, PLB2TAU, PLB1Double, PLB1Triple, and PLB4) were used to investigate if consistent alterations exist in multiple elements of the retinoic acid signaling pathway in these models. Many steps of the retinoic acid signaling pathway including binding proteins and metabolic enzymes decline, while the previously reported increase in RBP4 was only consistent at late (6 months) but not early (3 month) ages. The retinoic acid receptors were exceptional in their consistent decline in mRNA and protein with transcript decline of retinoic acid receptors β and γ by 3 months, before significant pathology, suggesting involvement in early stages of disease. Decline in RBP1 transcript may also be an early but not late marker of disease. The decline in the retinoic acid signaling system may therefore be a therapeutic target for AD and frontotemporal dementia. Thus, novel stable retinoic acid receptor modulators (RAR-Ms) activating multiple genomic and non-genomic pathways were probed for therapeutic control of gene expression in rat primary hippocampal and cortical cultures. RAR-Ms promoted the non-amyloidogenic pathway, repressed lipopolysaccharide induced inflammatory genes and induced genes with neurotrophic action. RAR-Ms had diverse effects on gene expression allowing particular RAR-Ms to be selected for maximal therapeutic effect. Overall the results demonstrated the early decline of retinoic acid signaling in AD and frontotemporal dementia models and the activity of stable and potent alternatives to retinoic acid as potential therapeutics.
维甲酸（Retinoic acid）先前被提议用于治疗阿尔茨海默病（AD）。在这里，使用了五种表达 AD 和额颞叶痴呆风险基因的转基因小鼠模型（即 PLB2APP、PLB2TAU、PLB1Double、PLB1Triple 和 PLB4），以研究这些模型中维甲酸信号通路的多个元素是否存在一致的改变。维甲酸信号通路的许多步骤，包括结合蛋白和代谢酶，都下降了，而之前报道的 RBP4 增加仅在晚期（6 个月）而不是早期（3 个月）一致。维甲酸受体异常，其 mRNA 和蛋白一致下降，3 个月前就出现了转录下降，提示与疾病的早期阶段有关。RBP1 转录本的下降也可能是早期但不是晚期疾病的标志物。因此，维甲酸信号系统的下降可能是 AD 和额颞叶痴呆的治疗靶点。因此，研究人员探索了新型稳定的维甲酸受体调节剂（RAR-Ms），以调节大鼠原代海马和皮质培养物中的基因表达，作为治疗方法。RAR-Ms 促进了非淀粉样蛋白形成途径，抑制了脂多糖诱导的炎症基因，并诱导具有神经营养作用的基因。RAR-Ms 对基因表达有不同的影响，允许选择特定的 RAR-Ms 以获得最大的治疗效果。总之，这些结果表明 AD 和额颞叶痴呆模型中维甲酸信号的早期下降，以及稳定和有效的维甲酸替代品作为潜在治疗药物的活性。
