Neurobiology Research and Drug Delivery, Department of Health Science and Technology, Aalborg University, Denmark.
Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
Mol Cell Neurosci. 2023 Sep;126:103880. doi: 10.1016/j.mcn.2023.103880. Epub 2023 Jul 16.
Niemann-Pick type C2 disease (NP-C2) is a fatal neurovisceral disorder caused by defects in the lysosomal cholesterol transporter protein NPC2. Consequently, cholesterol and other lipids accumulate within the lysosomes, causing a heterogeneous spectrum of clinical manifestations. Murine models are essential for increasing the understanding of the complex pathology of NP-C2. This study, therefore, aims to describe the neurovisceral pathology in the NPC2-deficient mouse model to evaluate its correlation to human NP-C2.
Npc2-/- mice holding the LST105 mutation were used in the present study (Npc2). Body and organ weight and histopathological evaluations were carried out in six and 12-week-old Npc2-/- mice, with a special emphasis on neuropathology. The Purkinje cell (PC) marker calbindin, the astrocytic marker GFAP, and the microglia marker IBA1 were included to assess PC degeneration and neuroinflammation, respectively. In addition, the pathology of the liver, lungs, and spleen was assessed using hematoxylin and eosin staining.
Six weeks old pre-symptomatic Npc2-/- mice showed splenomegaly and obvious neuropathological changes, especially in the cerebellum, where initial PC loss and neuroinflammation were evident. The Npc2-/- mice developed neurological symptoms at eight weeks of age, severely progressing until the end-stage of the disease at 12 weeks. At the end-stage of the disease, Npc2-/- mice were characterized by growth retardation, tremor, cerebellar ataxia, splenomegaly, foam cell accumulation in the lungs, liver, and spleen, brain atrophy, pronounced PC degeneration, and severe neuroinflammation.
The Npc2 mouse model resembles the pathology seen in NP-C2 patients and denotes a valuable model for increasing the understanding of the complex disease manifestation and is relevant for testing the efficacies of new treatment strategies.
尼曼-匹克 C 型 2 型疾病（NP-C2）是一种致命的神经内脏疾病，由溶酶体胆固醇转运蛋白 NPC2 的缺陷引起。因此，胆固醇和其他脂质在溶酶体中积累，导致临床表现呈异质性。鼠模型对于增加对 NP-C2 复杂病理学的理解至关重要。因此，本研究旨在描述 NPC2 缺陷型小鼠模型的神经内脏病理学，以评估其与人类 NP-C2 的相关性。
本研究使用携带 LST105 突变的 Npc2-/- 小鼠（Npc2）。对 6 周龄和 12 周龄的 Npc2-/- 小鼠进行体重和器官重量以及组织病理学评估，特别强调神经病理学。钙结合蛋白（calbindin）被用作浦肯野细胞（PC）标志物，胶质纤维酸性蛋白（GFAP）被用作星形胶质细胞标志物，离子钙结合蛋白 1（IBA1）被用作小胶质细胞标志物，分别用于评估 PC 变性和神经炎症。此外，使用苏木精和伊红染色评估肝脏、肺和脾脏的病理学。
6 周龄无症状前的 Npc2-/- 小鼠表现出脾肿大和明显的神经病理学变化，尤其是在小脑，小脑初始 PC 丢失和神经炎症明显。Npc2-/- 小鼠在 8 周龄时出现神经症状，病情严重进展，直至 12 周龄疾病终末期。在疾病终末期，Npc2-/- 小鼠的特征为生长迟缓、震颤、小脑共济失调、脾肿大、肺、肝和脾泡沫细胞堆积、脑萎缩、明显的 PC 变性和严重的神经炎症。
Npc2 小鼠模型类似于 NP-C2 患者的病理学表现，是增加对复杂疾病表现理解的有价值模型，并且与测试新治疗策略的疗效相关。
