Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin Côte Ste Catherine, Montreal, QC, H3A 2B4, Canada.
Department of Neurology and Neurosurgery, McGill University, 3755 University Street, Montreal, QC, H3A 2B4, Canada.
Cell Death Differ. 2018 Jul;25(7):1319-1335. doi: 10.1038/s41418-017-0043-x. Epub 2018 Jan 19.
Active cysteinyl protease Caspase-6 is associated with early Alzheimer and Huntington diseases. Higher entorhinal cortex and hippocampal Caspase-6 levels correlate with lower cognitive performance in aged humans. Caspase-6 induces axonal degeneration in human primary neuron cultures and causes inflammation and neurodegeneration in mouse hippocampus, and age-dependent memory impairment. To assess whether Caspase-6 causes damage to another neuronal system, a transgenic knock-in mouse overexpressing a self-activated form of Caspase-6 five-fold in the striatum, the area affected in Huntington disease, and 2.5-fold in the hippocampus and cortex, was generated. Detection of Tubulin cleaved by Caspase-6 confirmed Caspase-6 activity. The Caspase-6 expressing mice and control littermates were subjected to behavioral tests to assess Huntington disease-relevant psychiatric, motor, and cognitive deficits. Depression was excluded with the forced swim and sucrose consumption tests. Motor deficits were absent in the nesting, clasping, rotarod, vertical pole, gait, and open field analyzes. However, Caspase-6 mice developed age-dependent episodic and spatial memory deficits identified by novel object recognition, Barnes maze and Morris water maze assays. Neuron numbers were maintained in the striatum, hippocampus, and cortex. Microglia and astrocytes were increased in the hippocampal stratum lacunosum molecular and in the cortex, but not in the striatum. Synaptic mRNA profiling identified two differentially expressed genes in transgenic hippocampus, but none in striatum. Caspase-6 impaired synaptic transmission and induced neurodegeneration in hippocampal CA1 neurons, but not in striatal medium spiny neurons. These data revealed that active Caspase-6 in the striatal medium spiny neurons failed to induce inflammation, neurodegeneration or behavioral abnormalities, whereas active Caspase-6 in the cortex and hippocampus impaired episodic and spatial memories, and induced inflammation, neuronal dysfunction, and neurodegeneration. The results indicate age and neuronal subtype-dependent Caspase-6 toxicity and highlight the importance of targeting the correct neuronal subtype to identify underlying molecular mechanisms of neurodegenerative diseases.
活性半胱氨酸蛋白酶 Caspase-6 与早发性阿尔茨海默病和亨廷顿病有关。高龄人群中，内嗅皮层和海马 Caspase-6 水平较高与认知能力下降相关。Caspase-6 在人原代神经元培养物中诱导轴突变性，并导致小鼠海马体炎症和神经退行性变，以及与年龄相关的记忆障碍。为了评估 Caspase-6 是否对另一个神经元系统造成损伤，生成了一种转基因敲入小鼠，该小鼠在纹状体（亨廷顿病受影响的区域）中过度表达自我激活形式的 Caspase-6 五倍，在海马体和皮质中过度表达 Caspase-6 两倍半。通过检测 Caspase-6 切割的微管蛋白来确认 Caspase-6 的活性。将 Caspase-6 表达的小鼠和对照同窝仔鼠进行行为测试，以评估与亨廷顿病相关的精神、运动和认知缺陷。通过强迫游泳和蔗糖消耗测试排除了抑郁。在嵌套、扣紧、转棒、垂直杆、步态和旷场分析中没有发现运动缺陷。然而，Caspase-6 小鼠出现了年龄依赖性的情景和空间记忆缺陷，这通过新物体识别、巴恩斯迷宫和莫里斯水迷宫试验来识别。纹状体、海马体和皮质中的神经元数量保持不变。海马体的腔隙分子层和皮质中的小胶质细胞和星形胶质细胞增加，但纹状体中没有增加。突触 mRNA 谱分析确定了转基因海马体中两个差异表达的基因，但纹状体中没有。Caspase-6 损害了海马体 CA1 神经元的突触传递，并诱导其神经退行性变，但未损害纹状体中的中脑神经元。这些数据表明，纹状体中的活性 Caspase-6 未能诱导炎症、神经退行性变或行为异常，而皮质和海马体中的活性 Caspase-6 损害了情景和空间记忆，并诱导了炎症、神经元功能障碍和神经退行性变。结果表明 Caspase-6 具有年龄和神经元亚型依赖性毒性，并强调了针对正确的神经元亚型以确定神经退行性疾病潜在分子机制的重要性。
