Novel Nuclear Factor-KappaB Targeting Peptide Suppresses β-Amyloid Induced Inflammatory and Apoptotic Responses in Neuronal Cells

In the central nervous system (CNS), activation of the transcription factor nuclear factor-kappa B (NF-κβ) is associated with both neuronal survival and increased vulnerability to apoptosis. The mechanisms underlying these dichotomous effects are attributed to the composition of NF-κΒ dimers. In Alzheimer’s disease (AD), β-amyloid (Aβ) and other aggregates upregulate activation of p65:p50 dimers in CNS cells and enhance transactivation of pathological mediators that cause neuroinflammation and neurodegeneration. Hence selective targeting of activated p65 is an attractive therapeutic strategy for AD. Here we report the design, structural and functional characterization of peptide analogs of a p65 interacting protein, the glucocorticoid induced leucine zipper (GILZ). By virtue of binding the transactivation domain of p65 exposed after release from the inhibitory IκΒ proteins in activated cells, the GILZ analogs can act as highly selective inhibitors of activated p65 with minimal potential for off-target effects.

在中枢神经系统（central nervous system, CNS）中，转录因子核因子-κB（transcription factor nuclear factor-kappa B, NF-κβ）的激活既与神经元存活密切相关，又会增加细胞凋亡的易感性。上述两种截然相反的作用机制，均归因于NF-κΒ二聚体的组成差异。在阿尔茨海默病（Alzheimer’s disease, AD）中，β淀粉样蛋白（β-amyloid, Aβ）及其他聚集物可上调中枢神经系统细胞内p65:p50二聚体的激活水平，并增强病理介质的反式激活作用，进而诱发神经炎症与神经退行性变。因此，选择性靶向激活态p65成为颇具吸引力的阿尔茨海默病治疗策略。
本研究报道了p65相互作用蛋白——糖皮质激素诱导亮氨酸拉链（glucocorticoid induced leucine zipper, GILZ）的肽类类似物的设计、结构与功能表征。GILZ类似体通过结合激活细胞中从抑制性IκB蛋白释放后暴露的p65转录激活结构域，可作为激活态p65的高选择性抑制剂，且脱靶效应潜力极低。