Mohr_2012_Neuropharmacol_67C_37

An impaired central cholinergic system is at least partly involved in Alzheimer's disease (AD) pathogenesis, with cholinergic markers such as acetylcholinesterase (AChE) activity and protein levels decreasing as cognitive decline progresses. AD patients receive AChE inhibitor drugs to enhance cholinergic responses in the brain. The present study characterises the cholinergic system of mice heterozygous for AChE (HZ) as a suitable in vivo model for permanently reduced AChE activity. In comparison to homozygous, wild type (WT) mice, HZ mice show a 40% reduction of AChE activity in the brain, while their hippocampal ACh levels are increased by 56% as measured by microdialysis; choline acetyltransferase levels remain unaltered, and choline uptake increases 2-fold. We demonstrate that HZ mice are significantly more sensitive to local AChE inhibition (BW284c51), but remain insensitive to butyrylcholinesterase (BCHE) inhibition (bambuterol). HZ mice are also more sensitive to the peripheral application of the selective AChE inhibitor donepezil or the mixed inhibitor physostigmine; extracellular ACh levels rise significantly after administration of both drugs; also glucose levels are moderately increased indicating potentially non-cholinergic effects of donepezil. Behavioural tests show comparable cognitive function in both mouse strains. Our results are discussed in relation to the use of AChE/BCHE inhibitors in AD patients.