Department of Biomedical Engineering, Rensselaer Polytechnic Institute, Troy, NY, USA.
Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA.
J Alzheimers Dis. 2024;98(1):301-318. doi: 10.3233/JAD-230600.
Alzheimer's disease (AD) is characterized by disrupted proteostasis and macroautophagy (hereafter "autophagy"). The pharmacological agent suramin has known autophagy modulation properties with potential efficacy in mitigating AD neuronal pathology.
In the present work, we investigate the impact of forebrain neuron exposure to suramin on the Akt/mTOR signaling pathway, a major regulator of autophagy, in comparison with rapamycin and chloroquine. We further investigate the effect of suramin on several AD-related biomarkers in sporadic AD (sAD)-derived forebrain neurons.
Neurons differentiated from ReNcell neural progenitors were used to assess the impact of suramin on the Akt/mTOR signaling pathway relative to the autophagy inducer rapamycin and autophagy inhibitor chloroquine. Mature forebrain neurons were differentiated from induced pluripotent stem cells (iPSCs) sourced from a late-onset sAD patient and treated with 100μM suramin for 72 h, followed by assessments for amyloid-β, phosphorylated tau, oxidative/nitrosative stress, and synaptic puncta density.
Suramin treatment of sAD-derived neurons partially ameliorated the increased p-Tau(S199)/Tau ratio, and fully remediated the increased glutathione to oxidized nitric oxide ratio, observed in untreated sAD-derived neurons relative to healthy controls. These positive results may be due in part to the distinct increases in Akt/mTOR pathway mediator p-p70S6K noted with suramin treatment of both ReNcell-derived and iPSC-derived neurons. Longer term neuronal markers, such as synaptic puncta density, were unaffected by suramin treatment.
These findings provide initial evidence supporting the potential of suramin to reduce the degree of dysregulation in sAD-derived forebrain neurons in part via the modulation of autophagy.
阿尔茨海默病（AD）的特征是蛋白质稳态和巨自噬（以下简称“自噬”）受到破坏。药物苏拉明具有已知的自噬调节特性，有可能减轻 AD 神经元病变。
在本工作中，我们研究了前脑神经元暴露于苏拉明对 Akt/mTOR 信号通路的影响，该通路是自噬的主要调节剂，并与雷帕霉素和氯喹进行了比较。我们进一步研究了苏拉明对源自散发性 AD（sAD）的前脑神经元的几种 AD 相关生物标志物的影响。
使用从 ReNcell 神经祖细胞分化的神经元来评估苏拉明对 Akt/mTOR 信号通路的影响，与自噬诱导剂雷帕霉素和自噬抑制剂氯喹进行比较。从晚发性 sAD 患者来源的诱导多能干细胞（iPSC）分化成熟的前脑神经元，用 100μM 苏拉明处理 72 小时，然后评估淀粉样蛋白-β、磷酸化 tau、氧化/硝化应激和突触斑密度。
苏拉明处理 sAD 来源的神经元部分改善了未经处理的 sAD 来源的神经元中观察到的 p-Tau(S199)/Tau 比值增加，以及完全纠正了谷胱甘肽与氧化亚硝酸盐比值增加的现象，与健康对照组相比。这些积极的结果可能部分归因于苏拉明处理 ReNcell 衍生和 iPSC 衍生神经元时 Akt/mTOR 通路调节剂 p-p70S6K 的明显增加。较长时间的神经元标志物，如突触斑密度，不受苏拉明处理的影响。
这些发现提供了初步证据，支持苏拉明通过调节自噬，在一定程度上降低 sAD 来源的前脑神经元失调程度的潜力。
