Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 73, Issue 3, Pages 234-243Publisher
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0000000000000045
Keywords
Acetylcholinesterase inhibitor; Cholesterol; Cholinergic system; Donepezil; Neural stem cell Niemann Pick disease Type C; Purkinje neuron
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Funding
- Bio & Medical Technology Development Program of the National Research Foundation (NRF)
- Ministry of Science, ICT & Future Planning [2012M3A9C6049716]
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Neurodegenerative processes are often accompanied by disruption of cholinergic systems; therefore, acetylcholinesterase (AChE) inhibitors (AChEIs) may have therapeutic potential in some neurological conditions. We evaluated the effects of administration of donepezil, a widely used AChEI, in the cerebellum in a murine model of Niemann-Pick disease type C (NPC). The NPC mice developed Purkinje cell loss at the age of 8 weeks; 4-week-old NPC mice given donepezil led to improvement of Purkinje cell survival that was associated with improvement of motor dysfunction in the mice. Because abnormal accumulation of cholesterol caused by impaired lipid homeostasis is the principal pathogenetic mechanism underlying NPC, we investigated the effects of donepezil on cholesterol metabolism in the NPC mice. Donepezil treatment reduced cholesterol accumulation in adult neural stem cells in vitro, and it downregulated the expression of the cholesterol synthesis factors' sterol regulatory element-binding proteins and 3-hydroxy-3-methylglutaryl-CoA reductase in the cerebellum, implying that AChE activity might be associated with cholesterol homeostasis. Taken together, our findings suggest the role of a cholinergic pathway as a novel regulator of NPC progression and the potential application of AChEIs for the treatment of human NPC.
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