Tuberous sclerosis complex-1 (TSC1) contributes to selective neuronal vulnerability in Alzheimer's disease.

IF 4 2区医学 Q1 CLINICAL NEUROLOGY Neuropathology and Applied Neurobiology Pub Date : 2023-06-01 DOI:10.1111/nan.12904

Bryan A Adriaanse, Sinead Brady, Minghui Wang, Daniel J Beard, Jonathan I Spencer, Jonathan Pansieri, Brad A Sutherland, Margaret M Esiri, Alastair M Buchan, Zameel Cader, Bin Zhang, Gabriele C DeLuca

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Abstract

Aims: Selective neuronal vulnerability of hippocampal Cornu Ammonis (CA)-1 neurons is a pathological hallmark of Alzheimer's disease (AD) with an unknown underlying mechanism. We interrogated the expression of tuberous sclerosis complex-1 (TSC1; hamartin) and mTOR-related proteins in hippocampal CA1 and CA3 subfields.

Methods: A human post-mortem cohort of mild (n = 7) and severe (n = 10) AD and non-neurological controls (n = 9) was used for quantitative and semi-quantitative analyses. We also developed an in vitro TSC1 knockdown model in rat hippocampal neurons, and transcriptomic analyses of TSC1 knockdown neuronal cultures were performed.

Results: We found a selective increase of TSC1 cytoplasmic inclusions in human AD CA1 neurons with hyperactivation of one of TSC1's downstream targets, the mammalian target of rapamycin complex-1 (mTORC1), suggesting that TSC1 is no longer active in AD. TSC1 knockdown experiments showed accelerated cell death independent of amyloid-beta toxicity. Transcriptomic analyses of TSC1 knockdown neuronal cultures revealed signatures that were significantly enriched for AD-related pathways.

Conclusions: Our combined data point to TSC1 dysregulation as a key driver of selective neuronal vulnerability in the AD hippocampus. Future work aimed at identifying targets amenable to therapeutic manipulation is urgently needed to halt selective neurodegeneration, and by extension, debilitating cognitive impairment characteristic of AD.

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结节性硬化症复合体-1 (TSC1)与阿尔茨海默病的选择性神经元易感性有关。

目的:海马角氨(CA)-1神经元的选择性神经元易感性是阿尔茨海默病(AD)的病理标志，其潜在机制尚不清楚。我们检测了结节硬化复合物-1 (TSC1;海马CA1和CA3亚区mtor相关蛋白。方法:采用轻度AD (n = 7)和重度AD (n = 10)和非神经系统对照(n = 9)的人类死后队列进行定量和半定量分析。我们还在大鼠海马神经元中建立了体外TSC1敲除模型，并对TSC1敲除神经元进行了转录组学分析。结果:我们发现，在人AD CA1神经元中，TSC1胞质内含物选择性增加，同时TSC1的下游靶点之一，哺乳动物雷帕霉素复合物-1 (mTORC1)的过度激活，表明TSC1在AD中不再活跃。TSC1敲除实验显示，细胞死亡加速与淀粉样蛋白毒性无关。TSC1敲除神经元培养物的转录组学分析显示，ad相关通路显著富集。结论:我们的综合数据表明，TSC1失调是AD海马选择性神经元易感性的关键驱动因素。未来的工作迫切需要确定适合治疗操作的靶点，以阻止选择性神经退行性变，并进一步削弱AD特征的认知障碍。

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

Neuropathology and Applied Neurobiology 医学-病理学

CiteScore

8.20

自引率

2.00%

发文量

审稿时长

6-12 weeks

期刊介绍： Neuropathology and Applied Neurobiology is an international journal for the publication of original papers, both clinical and experimental, on problems and pathological processes in neuropathology and muscle disease. Established in 1974, this reputable and well respected journal is an international journal sponsored by the British Neuropathological Society, one of the world leading societies for Neuropathology, pioneering research and scientific endeavour with a global membership base. Additionally members of the British Neuropathological Society get 50% off the cost of print colour on acceptance of their article.