Sulforaphane prevents cognitive decline and mitochondrial failure induced by hippocampal expression of caspase-3 cleaved tau

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Neurochemistry international Pub Date : 2025-05-06 DOI:10.1016/j.neuint.2025.105991

Francisca Villavicencio-Tejo , Margrethe A. Olesen , Estibaliz Ampuero , Rodrigo A. Quintanilla

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引用次数: 0

Abstract

Caspase-3 cleaved tau (truncated tau) is a pathological modification in tau protein that contributes to neurofibrillary tangle formation (NFTs) and neurodegeneration in AD. Our previous studies indicate that truncated tau affects mitochondrial health, synaptic plasticity, and cognitive performance. Therefore, we studied the effects of sulforaphane (SFN), a natural compound activator of the NRF2 antioxidant pathway present in vegetables and sprouts, on neurodegeneration and cognitive decline induced by truncated tau expression in vivo.

We induced a 2-month hippocampal expression of GFP, full-length (AAV-Syn-GFP-T4) and truncated tau (AAV-Syn-GFP-T4C3) using a stereotaxic injection of adeno-associated-virus-9 (AAV9) linked to GFP and a synapsin neuronal promoter in tau (−/−) mice. Hippocampal tau-expressing mice were treated with SFN, and their cognitive performance (NOR, NOL, and Barnes maze tests) and hippocampal mitochondrial function were analyzed.

Interestingly, hippocampal truncated tau expression significantly affected cognitive and memory abilities, accompanied by increased ROS and severe mitochondrial dysfunction (depolarization, ATP loss, dynamics de-regulation). Notably, the treatment with SFN (50 mg/kg/day, i.p., two weeks) prevented cognitive impairment and reduced mitochondrial bioenergetics and dynamics defects induced by hippocampal truncated tau expression.

These findings suggest a potential role of SFN in ameliorating cognitive loss and mitochondrial impairment promoted by tau pathology in neurological disorders (NDs).

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萝卜硫素可预防海马表达caspase-3切割tau蛋白引起的认知能力下降和线粒体衰竭

Caspase-3 cleaved tau （truncated tau）是tau蛋白的一种病理修饰，有助于AD的神经原纤维缠结形成（nft）和神经退行性变。我们之前的研究表明，截短的tau影响线粒体健康、突触可塑性和认知表现。因此，我们研究了萝卜硫素（SFN），一种存在于蔬菜和豆芽中NRF2抗氧化途径的天然化合物激活剂，对体内tau蛋白表达截断引起的神经变性和认知能力下降的影响。我们在tau（−/−）小鼠中使用立体定向注射与GFP和突触神经元启动子连接的腺相关病毒-9 （AAV9）诱导GFP、全长（AAV-Syn-GFP-T4）和截短tau （AAV-Syn-GFP-T4C3）的海马表达2个月。用SFN治疗海马tau表达小鼠，分析其认知表现（NOR、NOL和Barnes迷宫测试）和海马线粒体功能。有趣的是，海马截断的tau表达显著影响认知和记忆能力，并伴有ROS增加和严重的线粒体功能障碍（去极化、ATP丢失、动态去调节）。值得注意的是，SFN治疗（50 mg/kg/天，ig，两周）可以预防认知障碍，减少海马tau蛋白表达截断引起的线粒体生物能量学和动力学缺陷。这些发现表明SFN在改善神经系统疾病（NDs）中tau病理引起的认知丧失和线粒体损伤中的潜在作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neurochemistry international 医学-神经科学

CiteScore

8.40

自引率

2.40%

发文量

128

审稿时长

37 days

期刊介绍： Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.