Donepezil enhances Purkinje cell survival and improves motor dysfunction by inhibiting cholesterol synthesis in a murine model of Niemann Pick type C disease

donepezil;Niemann Pick disease Type C;acetyl cholinesterase inhibitor;Purkinje cell;cholinergic neuron;cholesterol;636

수의과대학 협동과정 ;

University:서울대학교 대학원

关键词: donepezil;    Niemann Pick disease Type C;    acetyl cholinesterase inhibitor;    Purkinje cell;    cholinergic neuron;    cholesterol;    636;   

Others  :  http://s-space.snu.ac.kr/bitstream/10371/135023/1/000000013504.pdf

美国|英语

来源: Seoul National University Open Repository

【 摘 要 】

Acetylcholine (ACh) plays various roles in the process of neural differentiation and maturation as well as in the maintenance of the cognitive function. The neurodegenerative process is often accompanied by the disruption of the cholinergic system. In this study, we aimed to elucidate the importance of cholinergic pathway to maintain cerebellar integrity using murine model of Niemann-Pick disease type C (NPC), one of the incurable lyosomal storage disorders accompanied with neurological symptoms. Choline acetyltransferase (ChAT) immunostaining has shown that ACh activity was significantly reduced in the cerebellar cortex of NPC mice, where the pathognomonic Purkinje cell loss occurs. We then administrated acetylcholinesterase inhibitor (AChEI), Donepezil, for 4 weeks to compensate the attenuated cholinergic system. When NPC mice were treated with Donepezil, more Calbindin (CBD) positive Purkinje neurons survived during disease progress. In the rota-rod test, the performance of NPC mice was remarkably improved than that of control mice. To investigate the relationship between cholesterol accumulation and Purkinje neuronal survival, wild-type neural stem cells were treated with U18666A, a drug induces abnormal cholesterol accumulation similar to NPC state then were stained with filipin in vitro. It is noted that the number of filipin-positive cholesterol accumulated cells was reduced by Donepezil treatment. Improtantly, we found that Donepezil readily down-regulated mRNA levels of cholesterol synthesis molecules in vivo, implying that Ach might be related to the cholesterol homeostasis. Taken together, our findings suggest cholinergic pathway as another important regulator in NPC progress and propose the therapeutic application of AChEIs in NPC.