TDP-43蛋白病,最初在肌萎缩侧索硬化症(ALS)和额颞叶痴呆(FTD)中公开,在各种神经退行性疾病中与tau蛋白病共存,称为多病因痴呆(MEDs),包括阿尔茨海默病(AD)。虽然TDP-43的这种共病与恶化的神经变性和更陡的认知衰退密切相关,加剧的神经元丢失的致病机制仍然难以捉摸。在症状前ALS-FTD个体中发生的TDP-43剪接抑制的丧失表明这种早期丧失可以促进tau的病理性转化以加速神经元丧失。这里,我们报道,前脑神经元(CaMKII-CreER;Tardbpf/f小鼠)中TDP-43对隐性外显子的抑制缺失,是通过使脆弱神经元对caspase3依赖性内源性tau分裂敏感从而促进tau病变而加剧tau病变依赖性脑萎缩所必需的.在人类背景下证实了这一发现,我们证明,iPSC来源的皮质神经元中TDP-43功能的丧失促进了早期的隐性外显子包涵体和随后的caspase3介导的tau内蛋白水解.使用遗传方法在CaMKII-CreER中种子tau蛋白病;Tardbpf/f小鼠通过表达人tau的四重复微管结合结构域,我们表明,tau种子的数量与caspase3切割的tau水平呈正相关。重要的是,我们发现海马神经元对TDP-43耗竭的脆弱性取决于caspase3切割的tau的数量:来自CA2/3中最脆弱的神经元,其次是齿状回中的神经元,在CA1中最少。一起来看,我们的研究结果强烈支持以下观点:TDP-43功能丧失通过增加易损神经元对caspase3介导的tau内蛋白水解的敏感性来加剧tau蛋白病依赖性脑萎缩,导致与tau和TDP-43共病的人类疾病中更大程度的神经变性。因此,我们的工作公开了具有TDP-43共同病理学的人类tau蛋白病变的新机理见解和治疗靶标,并提供了用于测试治疗策略的新MED模型。
■对于小鼠大脑和人iPSC衍生的皮质神经元中D421处的tau的caspase3依赖性内蛋白水解,必须丧失TDP-43对隐蔽外显子的抑制。tau的胱天蛋白酶3依赖性裂解水平是缺乏TDP-43的小鼠大脑神经元易损性的主要决定因素。在多病因痴呆的新型小鼠模型中,TDP-43功能丧失通过使脆弱的神经元对半胱天冬酶3介导的tau内蛋白水解敏感来驱动tau病变,从而加剧tau病变依赖性脑萎缩。在具有TDP-43共病的人类tau蛋白病中,TDP-43的功能障碍可能会促进脆弱神经元中内源性tau的caspase3依赖性裂解,并加剧tau蛋白病依赖性神经变性。
■TDP-43抑制功能丧失加剧多病因痴呆(MED)中tau蛋白病变依赖性神经变性的致病机制尚不清楚。在一个新的MED小鼠模型中,TDP-43功能的丧失通过使脆弱的神经元对内源性tau蛋白的caspase3依赖性裂解敏感来驱动tau蛋白病变,从而加剧tau蛋白病变依赖性脑萎缩。这种机械洞察力为具有tau和TDP-43共病的MED提供了新的靶标和治疗策略,可以使用这种MED小鼠模型进行验证。
TDP-43 proteinopathy, initially disclosed in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, termed multiple etiology dementias (MEDs), including Alzheimer\'s Disease (AD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration and steeper cognitive decline, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. The loss of TDP-43 splicing repression that occurs in presymptomatic ALS-FTD individuals suggests that such early loss could facilitate the pathological conversion of tau to accelerate neuron loss. Here, we report that the loss of TDP-43 repression of cryptic exons in forebrain neurons (CaMKII-CreER;Tardbp f/f mice) is necessary to exacerbate tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to
caspase 3-dependent cleavage of endogenous tau to promote tauopathy. Corroborating this finding within the human context, we demonstrate that loss of TDP-43 function in iPSC-derived cortical neurons promotes early cryptic exon inclusion and subsequent
caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER;Tardbp f/f mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed positively correlates with levels of
caspase 3-cleaved tau. Importantly, we found that the vulnerability of hippocampal neurons to TDP-43 depletion is dependent on the amount of
caspase 3-cleaved tau: from most vulnerable neurons in the CA2/3, followed by those in the dentate gyrus, to the least in CA1. Taken together, our findings strongly support the view that TDP-43 loss-of-function exacerbates tauopathy-dependent brain atrophy by increasing the sensitivity of vulnerable neurons to
caspase 3-mediated endoproteolysis of tau, resulting in a greater degree of neurodegeneration in human disorders with co-pathologies of tau and TDP-43. Our work thus discloses novel mechanistic insights and therapeutic targets for human tauopathies harboring co-pathology of TDP-43 and provides a new MED model for testing therapeutic strategies.