四面体框架核酸抑制 Aβ介导的铁死亡，改善阿尔茨海默病中的认知和突触损伤。

BACKGROUND: Ferroptosis represents a nonapoptotic type of programmed cell death induced by excessive intracellular iron accumulation. Ferroptosis is an essential driver of the pathogenesis of Alzheimer's disease (AD). Tetrahedral framework nucleic acids (tFNAs) are a novel type of nanoparticle with superior antiapoptotic capacity and excellent biocompatibility. However, the effect of tFNAs on Aβ triggered ferroptosis, cognitive and synaptic impairments in AD remains unknown. METHODS: N2a cells were treated with Aβ combined with/without tFNAs. Cell viability and levels of Fe, lipid peroxidation, MDA, LDH, and GSH were examined. RNA sequencing was applied to explore dysregulated ferroptosis related genes. Seven-month-old APP/PS1 mice were intranasally administrated with tFNAs for two weeks. Fluorescence imaging was used to detect the tFNAs distribution in the brain. Novel object recognition (NOR) test followed by Morris water maze (MWM) was used to test the learning and memory performance of mice. Golgi staining, Western blot, and immunofluorescence staining were used to examine synaptic plasticity. RESULTS: tFNAs promoted cell viability and GSH levels, reduced the levels of Fe, lipid peroxidation, MDA, and LDH in N2a cells treated with Aβ. RNA sequencing revealed that tFNAs reversed the promotive effect of Aβ on ferroptosis driver Atf3 gene and suppressive effect on ferroptosis suppressors Rrm2 and Furin genes. Fluorescence imaging confirmed the brain infiltration of tFNAs. tFNAs rescued synaptic and memory impairments, and ferroptosis in seven-month-old APP/PS1 mice. CONCLUSIONS: Collectively, tFNAs inhibited Aβ-mediated ferroptosis and ameliorated cognitive and synaptic impairments in AD mice. tFNAs may serve as novel option to deal with AD.

背景：铁死亡是一种由细胞内铁积累过多引起的非凋亡程序性细胞死亡。铁死亡是阿尔茨海默病（AD）发病机制的关键驱动因素。四面体框架核酸（tFNAs）是一种新型纳米颗粒，具有优异的抗凋亡能力和良好的生物相容性。然而，tFNAs 对 Aβ 触发的铁死亡、AD 认知和突触损伤的影响尚不清楚。

方法：用 Aβ 联合/不联合 tFNAs 处理 N2a 细胞。检测细胞活力和铁、脂质过氧化、MDA、LDH 和 GSH 水平。应用 RNA 测序探讨失调的铁死亡相关基因。用 tFNAs 对 7 月龄 APP/PS1 小鼠进行鼻腔内给药 2 周。荧光成像用于检测 tFNAs 在大脑中的分布。用新物体识别（NOR）测试和 Morris 水迷宫（MWM）测试检测小鼠的学习和记忆能力。高尔基染色、Western blot 和免疫荧光染色用于检测突触可塑性。

结果：tFNAs 促进了 Aβ 处理的 N2a 细胞的活力和 GSH 水平，降低了铁、脂质过氧化、MDA 和 LDH 水平。RNA 测序显示，tFNAs 逆转了 Aβ 对铁死亡驱动基因 Atf3 的促进作用，以及对铁死亡抑制基因 Rrm2 和 Furin 的抑制作用。荧光成像证实了 tFNAs 向大脑渗透。tFNAs 挽救了 7 月龄 APP/PS1 小鼠的突触和记忆损伤以及铁死亡。

结论：综上所述，tFNAs 抑制了 Aβ 介导的铁死亡，改善了 AD 小鼠的认知和突触损伤。tFNAs 可能成为治疗 AD 的新选择。