MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in ALS-FTD
MRI-guided histology of TDP-43 knock-in mice implicates parvalbumin interneuron loss, impaired neurogenesis and aberrant neurodevelopment in ALS-FTD
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DOI：
10.1101/2020.05.24.107177
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发表时间：
2020-05
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通讯作者：
Ziqiang Lin;Eugene Kim;Mohi Ahmed;Gang Han;C. Simmons;Yushi T. Redhead;Jack Bartlett;Luis Emiliano
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文献类型：
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作者：
Ziqiang Lin;Eugene Kim;Mohi Ahmed;Gang Han;C. Simmons;Yushi T. Redhead;Jack Bartlett;Luis Emiliano
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）是重叠的神经退行性疾病，越来越多地被认为具有长的前驱期。对这些早期阶段的研究有望产生有价值的疾病生物标志物，并将成为了解ALS-FTD发生机制的关键。在此，我们使用体内磁共振成像（MRI）、组织学和计算机断层扫描来识别ALS-FTD TDP-43 Q331 K基因敲入小鼠模型中早期疾病的结构和细胞读数。成年突变小鼠表现出脑实质体积减少，影响额叶和内嗅皮质，其方式与ALS-FTD相似。皮质下、小脑和脑干区域也受到影响，与症状前C9 orf 72突变携带者的观察结果一致，C9 orf 72是ALS和FTD最常见的遗传原因。通过MRI测量，还在海马齿状回（DG）中观察到体积损失，并沿着心室扩大。在这些成像结果的指导下，详细的死后脑组织分析显示，减少的小白蛋白阳性（PV+）中间神经元作为突变小鼠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DG中发现未成熟神经元减少，表明成年神经发生受损，而幼年突变小鼠（P14）中PV+中间神经元缺乏表明TDP-43 Q331 K破坏了神经发育。计算机断层扫描成像也显示突变体的头骨形态发生了改变，进一步表明TDP-43 Q331 K在发育中的作用。最后，对人类死后前额皮质的分析证实，在散发性ALS和与C9 orf 72突变相关的ALS病例中，前额皮质中PV+中间神经元缺乏。本研究表明PV+中间神经元在与ALS-FTD相关的局部脑易损性中发挥重要作用，并确定了新的MRI和组织学生物标志物，这些生物标志物在评估TDP-43 Q331 K基因敲入小鼠中推定治疗剂的疗效方面具有价值。
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping neurodegenerative diseases that are increasingly understood to have long prodromal periods. Investigation of these early stages promises to yield valuable biomarkers of disease and will be key to understanding mechanisms underlying the genesis of ALS-FTD. Here, we use in vivo magnetic resonance imaging (MRI), histology and computed tomography to identify structural and cellular readouts of early stage disease in the TDP-43Q331K knock-in mouse model of ALS-FTD. Adult mutant mice demonstrated parenchymal volume reductions affecting the frontal lobe and entorhinal cortex in a manner reminiscent of ALS-FTD. Subcortical, cerebellar and brain stem regions were also affected in line with observations in presymptomatic carriers of mutations in C9orf72, the commonest genetic cause of both ALS and FTD. Volume loss, as measured by MRI, was also observed in the dentate gyrus (DG) of the hippocampus, along with ventricular enlargement. Guided by these imaging findings, detailed post-mortem brain tissue analysis revealed reduced parvalbumin-positive (PV+) interneurons as a potential cellular correlate of MRI changes in mutant mice. By contrast, microglia were in a disease activated state even in the absence of brain volume loss. A reduction in immature neurons was found in the DG, indicative of impaired adult neurogenesis, while a paucity of PV+ interneurons in juvenile mutant mice (P14) suggests that TDP-43Q331K disrupts neurodevelopment. Computerised tomography imaging also showed altered skull morphology in mutants, further suggesting a role for TDP-43Q331K in development. Finally, analysis of human post-mortem prefrontal cortices confirmed a paucity of PV+ interneurons in the prefrontal cortex in cases with both sporadic ALS and ALS linked to C9orf72 mutations. This study suggests an important role for PV+ interneurons in regional brain vulnerability associated with ALS-FTD, and identifies novel MRI and histological biomarkers that will be of value in assessing the efficacy of putative therapeutics in TDP-43Q331K knock-in mice.