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

J Neuropathol Exp Neurol. 2014 Mar;73(3):234-43. doi: 10.1097/NEN.0000000000000045.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Adult Stem Cells / drug effects
  • Animals
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cerebellum / pathology*
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use*
  • Disease Models, Animal
  • Donepezil
  • Gene Expression Regulation / drug effects
  • Humans
  • Indans / pharmacology
  • Indans / therapeutic use*
  • Intracellular Signaling Peptides and Proteins
  • Lateral Ventricles / cytology
  • Liver X Receptors
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Movement Disorders / drug therapy*
  • Movement Disorders / etiology*
  • Mutation / genetics
  • Niemann-Pick Disease, Type C / complications*
  • Niemann-Pick Disease, Type C / drug therapy
  • Niemann-Pick Disease, Type C / genetics
  • Niemann-Pick Disease, Type C / pathology
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / metabolism
  • Piperidines / pharmacology
  • Piperidines / therapeutic use*
  • Proteins / genetics
  • Psychomotor Performance / drug effects
  • Purkinje Cells / drug effects*
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Sterol Regulatory Element Binding Protein 2 / genetics
  • Sterol Regulatory Element Binding Protein 2 / metabolism

Substances

  • ATP-Binding Cassette Transporters
  • Cholinesterase Inhibitors
  • Indans
  • Intracellular Signaling Peptides and Proteins
  • Liver X Receptors
  • Npc1 protein, mouse
  • Orphan Nuclear Receptors
  • Piperidines
  • Proteins
  • Srebf1 protein, mouse
  • Srebf2 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Donepezil