Troriluzole rescues glutamatergic deficits, amyloid and tau pathology, and synaptic and memory impairments in 3xTg-AD mice.

IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Jeremiah Pfitzer, Priyanka D Pinky, Savannah Perman, Emma Redmon, Luca Cmelak, Vishnu Suppiramaniam, Vladimir Coric, Irfan A Qureshi, Michael W Gramlich, Miranda N Reed
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引用次数: 0

Abstract

Alzheimer's disease (AD) is a neurodegenerative condition in which clinical symptoms are highly correlated with the loss of glutamatergic synapses. While later stages of AD are associated with markedly decreased glutamate levels due to neuronal loss, in the early stages, pathological accumulation of glutamate and hyperactivity contribute to AD pathology and cognitive dysfunction. There is increasing awareness that presynaptic dysfunction, particularly synaptic vesicle (SV) alterations, play a key role in mediating this early-stage hyperactivity. In the current study, we sought to determine whether the 3xTg mouse model of AD that exhibits both beta-amyloid (Aβ) and tau-related pathology would exhibit similar presynaptic changes as previously observed in amyloid or tau models separately. Hippocampal cultures from 3xTg mice were used to determine whether presynaptic vesicular glutamate transporters (VGlut) and glutamate are increased at the synaptic level while controlling for postsynaptic activity. We observed that 3xTg hippocampal cultures exhibited increased VGlut1 associated with an increase in glutamate release, similar to prior observations in cultures from tau mouse models. However, the SV pool size was also increased in 3xTg cultures, an effect not previously observed in tau mouse models but observed in Aβ models, suggesting the changes in pool size may be due to Aβ and not tau. Second, we sought to determine whether treatment with troriluzole, a novel 3rd generation tripeptide prodrug of the glutamate modulator riluzole, could reduce VGlut1 and glutamate release to restore cognitive deficits in 8-month-old 3xTg mice. Treatment with troriluzole reduced VGlut1 expression, decreased basal and evoked glutamate release, and restored cognitive deficits in 3xTg mice. Together, these findings suggest presynaptic alterations are early events in AD that represent potential targets for therapeutic intervention, and these results support the promise of glutamate-modulating drugs such as troriluzole in Alzheimer's disease.

曲利卢唑可挽救 3xTg-AD 小鼠的谷氨酸能缺陷、淀粉样蛋白和 tau 病理学以及突触和记忆损伤。
阿尔茨海默病(AD)是一种神经退行性疾病,其临床症状与谷氨酸能突触的丧失密切相关。阿尔茨海默病晚期由于神经元缺失,谷氨酸水平明显下降,而在早期,谷氨酸的病理性积累和亢进会导致阿尔茨海默病的病理变化和认知功能障碍。越来越多的人认识到,突触前功能障碍,尤其是突触小泡(SV)的改变,在介导这种早期亢进中起着关键作用。在本研究中,我们试图确定同时表现出β-淀粉样蛋白(Aβ)和tau相关病理变化的3xTg小鼠AD模型是否会表现出与之前在淀粉样蛋白或tau模型中分别观察到的类似突触前变化。我们使用 3xTg 小鼠的海马培养物来确定突触前囊泡谷氨酸转运体(VGlut)和谷氨酸是否在突触水平增加,同时控制突触后活动。我们观察到,3xTg 海马培养物表现出与谷氨酸释放增加相关的 VGlut1 增加,这与之前在 tau 小鼠模型培养物中观察到的结果类似。然而,3xTg 培养物中 SV 池的大小也增加了,这是之前在 tau 小鼠模型中没有观察到的,但在 Aβ 模型中观察到了,这表明池大小的变化可能是由于 Aβ 而不是 tau 引起的。其次,我们试图确定使用谷氨酸调节剂利鲁唑的新型第三代三肽原药曲利鲁唑治疗是否能减少 VGlut1 和谷氨酸的释放,从而恢复 8 个月大的 3xTg 小鼠的认知障碍。使用曲利卢唑治疗可减少 VGlut1 的表达,降低谷氨酸的基础释放和诱发释放,并恢复 3xTg 小鼠的认知障碍。这些发现共同表明突触前改变是阿兹海默病的早期事件,是治疗干预的潜在靶点,这些结果支持了谷氨酸调节药物(如曲利卢唑)治疗阿兹海默病的前景。
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
Journal of Neurochemistry
Journal of Neurochemistry 医学-神经科学
CiteScore
9.30
自引率
2.10%
发文量
181
审稿时长
2.2 months
期刊介绍: Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.
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