MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia.
MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in amyotrophic lateral sclerosis-frontotemporal dementia.
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DOI：
10.1093/braincomms/fcab114
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发表时间：
2021
影响因子：
4.8
通讯作者：
Sreedharan J
中科院分区：
文献类型：
--
作者：
Lin Z;Kim E;Ahmed M;Han G;Simmons C;Redhead Y;Bartlett J;Pena Altamira LE;Callaghan I;White MA;Singh N;Sawiak S;Spires-Jones T;Vernon AC;Coleman MP;Green J;Henstridge C;Davies JS;Cash D;Sreedharan J
肌萎缩侧索硬化症和额颞痴呆是重叠的疾病，MRI在症状出现之前就显示了脑结构的变化。在临床前模型中总结这些变化将有助于我们更好地理解早期疾病中区域性选择性脑萎缩背后的分子原因。因此，我们使用MRI研究了TDP-43Q331K敲入小鼠的肌萎缩侧索硬化症-额颞部痴呆模型的翻译潜力。我们对TDP-43Q331K基因敲除小鼠进行了体内MRI检查。选择有显著体积变化的区域进行尸检脑组织分析。采用体外计算机断层扫描观察颅骨形态。对死后肌萎缩侧索硬化症患者额叶皮质中的小白蛋白神经元密度进行定量。成年突变者表现出影响额叶和内嗅皮质的实质体积减少，这让人联想到肌萎缩侧索硬化症-额颞叶痴呆。皮质下、小脑和脑干区域也受到影响，这与C9orf72突变的症状前携带者的观察结果一致。C9orf72是肌萎缩侧索硬化症和额颞叶痴呆的最常见遗传原因。随着脑室扩大，海马齿状回的体积也减少了。免疫组织化学显示，小白蛋白中间神经元减少是突变小鼠MRI变化的潜在细胞相关性。相比之下，即使在没有脑容量损失的情况下，小胶质细胞也处于疾病激活状态。在齿状回中发现未成熟神经元的减少，这表明成年神经发生受损，而P14突变小鼠中少量的小白蛋白中间神经元表明TDP-43Q331K干扰了神经发育。计算机断层成像显示，突变体的头骨形态发生了变化，进一步表明TDP-43Q331K在发育中发挥了作用。最后，对人类死后大脑的分析证实，散发性肌萎缩侧索硬化症和与C9orf72突变相关的肌萎缩侧索硬化症患者的前额叶皮质中缺少小白蛋白中间神经元。在TDP-43Q331K敲入小鼠中，重现了在人类肌萎缩侧索硬化症-额颞部痴呆中看到的局部脑MRI变化。通过将活体成像与靶向组织学相结合，我们可以揭开人类疾病选择性大脑脆弱性潜在的细胞和分子过程。除了帮助了解疾病的最早原因，我们的MRI和组织学标记物将在评估TDP-43Q331K敲入小鼠的假定疗法的有效性方面具有价值。Lin、Kim和他的同事使用MRI来研究TDP-43Q331K敲入小鼠的变化，这些变化类似于症状前人类肌萎缩侧索硬化症-额颞痴呆。一项组织学调查表明，小白蛋白神经元间质丢失、神经发生受损、小胶质细胞激活和异常神经发育在疾病发病机制中具有一定的意义。他们证实了人类肌萎缩侧索硬化症中的小白蛋白中间神经元减少。
Amyotrophic lateral sclerosis and frontotemporal dementia are overlapping diseases in which MRI reveals brain structural changes in advance of symptom onset. Recapitulating these changes in preclinical models would help to improve our understanding of the molecular causes underlying regionally selective brain atrophy in early disease. We therefore investigated the translational potential of the TDP-43Q331K knock-in mouse model of amyotrophic lateral sclerosis-frontotemporal dementia using MRI. We performed in vivo MRI of TDP-43Q331K knock-in mice. Regions of significant volume change were chosen for post-mortem brain tissue analyses. Ex vivo computed tomography was performed to investigate skull shape. Parvalbumin neuron density was quantified in post-mortem amyotrophic lateral sclerosis frontal cortex. Adult mutants demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of amyotrophic lateral sclerosis-frontotemporal dementia. Subcortical, cerebellar and brain stem regions were also affected in line with observations in pre-symptomatic carriers of mutations in C9orf72, the commonest genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia. Volume loss was also observed in the dentate gyrus of the hippocampus, along with ventricular enlargement. Immunohistochemistry revealed reduced parvalbumin interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia was in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the dentate gyrus, indicative of impaired adult neurogenesis, while a paucity of parvalbumin interneurons in P14 mutant mice suggests that TDP-43Q331K disrupts neurodevelopment. Computerized tomography imaging showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem brains confirmed a paucity of parvalbumin interneurons in the prefrontal cortex in sporadic amyotrophic lateral sclerosis and amyotrophic lateral sclerosis linked to C9orf72 mutations. Regional brain MRI changes seen in human amyotrophic lateral sclerosis-frontotemporal dementia are recapitulated in TDP-43Q331K knock-in mice. By marrying in vivo imaging with targeted histology, we can unravel cellular and molecular processes underlying selective brain vulnerability in human disease. As well as helping to understand the earliest causes of disease, our MRI and histological markers will be valuable in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice. Lin, Kim and colleagues use MRI to appreciate changes in TDP-43Q331K knock-in mice akin to those seen in presymptomatic human amyotrophic lateral sclerosis-frontotemporal dementia. A histological survey implicates parvalbumin interneuron loss, impaired neurogenesis, microglial activation and aberrant neurodevelopment in disease pathogenesis. They confirm reduced parvalbumin interneurons in human amyotrophic lateral sclerosis.
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