Ganglioside Nanocluster-Targeting Peptidyl Inhibitor Prevents Amyloid β Fibril Formation on the Neuronal Membrane
Ganglioside Nanocluster-Targeting Peptidyl Inhibitor Prevents Amyloid β Fibril Formation on the Neuronal Membrane
复制标题
神经节苷脂纳米簇靶向肽基抑制剂可防止神经元膜上淀粉样蛋白 β 原纤维的形成
DOI：
10.1021/acschemneuro.2c00047
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发表时间：
2022
影响因子：
5
通讯作者：
Sato Toshinori
中科院分区：
文献类型：
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作者：
Matsubara Teruhiko;Nakai Mako;Nishihara Masaya;Miyamoto Erika;Sato Toshinori
由肽和蛋白质聚集体引起的神经毒性与神经退行性疾病的发作相关。由神经元神经节苷脂富集的纳米结构域（纳米簇）诱导的β淀粉样蛋白（Aβ）在突触前神经元膜中的积累，导致毒性寡聚体和纤维形式，与阿尔茨海默病（AD）的发病有关。在目前的研究中，我们发现神经节苷脂簇结合肽（GCBP），一种与富含神经节苷脂的纳米簇结合的十五肽VWRLLAPPFSNRLLP，抑制Aβ组装体的形成，IC 50为12 pM，并清除沉积在脂质膜上的Aβ纤维。因此，除了抑制Aβ组装体形成外，GCBP还有效清除毒性Aβ组装体，从而抑制由此类组装体诱导的神经元细胞损伤和死亡。这些结果表明，神经节苷脂簇结合分子可能作为一种新的Aβ靶向药物，具有独特的作用机制，可用于改善AD。
Neurotoxicity caused by peptide and protein aggregates is associated with the onset of neurodegenerative diseases. Accumulation of the amyloid β protein (Aβ) induced by neuronal ganglioside-enriched nanodomains (nanoclusters) in the presynaptic neuronal membrane, resulting in toxic oligomeric and fibrous forms, is implicated in the onset of Alzheimer’s disease (AD). In the current study, we found that the ganglioside cluster-binding peptide (GCBP), a pentadecapeptide VWRLLAPPFSNRLLP that binds to ganglioside-enriched nanoclusters, inhibits the formation of Aβ assemblies with an IC50of 12 pM and also removes Aβ fibrils deposited on the lipid membrane. Thus, in addition to inhibiting Aβ assembly formation, GCBP effectively clears toxic Aβ assemblies as well, thereby suppressing neuronal cellular damage and death induced by such assemblies. These results indicate that ganglioside cluster-binding molecules may act as novel Aβ-targeting drugs with a unique mechanism of action that may be utilized to ameliorate AD.