背景:Niemann-PickC2型疾病(NP-C2)是一种由溶酶体胆固醇转运蛋白NPC2缺陷引起的致命性神经内脏疾病。因此,胆固醇和其他脂质在溶酶体内积累,导致临床表现的异质性。鼠模型对于增加对NP-C2复杂病理的理解至关重要。这项研究,因此,目的描述NPC2缺陷小鼠模型中的神经内脏病理学,以评估其与人NP-C2的相关性。
方法:本研究使用携带LST105突变的Npc2-/-小鼠(Npc2Gt(LST105)BygNya)。在六只和12周龄的Npc2-/-小鼠中进行了身体和器官重量以及组织病理学评估,特别强调神经病理学。浦肯野细胞(PC)标记calbindin,星形细胞标记GFAP,和小胶质细胞标志物IBA1被纳入评估PC变性和神经炎症,分别。此外,肝脏的病理学,肺,使用苏木精和伊红染色评估脾脏。
结果:6周龄症状前的Npc2-/-小鼠表现出脾肿大和明显的神经病理变化,尤其是小脑,其中最初的PC损失和神经炎症是明显的。Npc2-/-小鼠在8周龄时出现神经症状,严重进展,直到12周时疾病的末期。在疾病的末期,Npc2-/-小鼠的特征是生长迟缓,震颤,小脑共济失调,脾肿大,泡沫细胞在肺部积聚,肝脏,和脾脏,脑萎缩,明显的PC变性,和严重的神经炎症.
结论:Npc2Gt(LST105)BygNya小鼠模型与NP-C2患者的病理相似,是增加对复杂疾病表现的理解的有价值的模型,并且与测试新治疗策略的有效性相关。
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 (Npc2Gt(LST105)BygNya). 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 Npc2Gt(LST105)BygNya 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.