Acetylcholinesterase (ACHE) is the enzyme which is responsible for the breakdown of the neurotransmitter, acetylcholine (ACh), in cholinergic synapses. In the brain, ACh subserves important functions e.g. for attention, learning and memory. Central cholinergic neurons which innervate cortex and hippocampus are typically degenerating during Alzheimer's disease; this process is accompanied by attention and memory deficits in Alzheimer patients. In the present proposal, we suggest to investigate central cholinergic functions in genetically modified mice which are deficient for ACHE. These mice have body tremor and are prone to seizures, observations which are compatible with an excess of ACh due to lack of enzymatic breakdown.
The first aim of our study is to quantify extracellular levels of ACh in the brain of AChE-deficient mice compared to heterozygous mice and control mice. For this purpose, we will use the microdialysis technique adapted to mice. We will also measure high-affinity choline uptake to determine possible compensatory changes of ACh turnover in cholinergic neurons. However, the fact that AChE-deficient mice are alive suggests that other pathways may exist to break down ACh. Butyrylcholinesterase (BChE), an enzyme associated with glial cells in the brain but of unknown function, is known to hydrolyze ACh at slow rates. We hypothesize that BChE hydrolyzes ACh in AChE-deficient mice thereby making them viable.
Our second aim therefore is to test changes of extracellular ACh in the brain upon application of specific inhibitors of AChE or BChE. Our results will show to what extent the brain can compensate for the loss of ACHE; this is also of interest for intoxications of humans with organophosphates (nerve gases). We will also determine to what extent BChE can substitute for AChE in the brain. Our results will show if inhibitors of BChE may be useful for the treatment of Alzheimer's disease. BChE inhibitors would be expected to increase brain ACh in Alzheimer patients in the absence of peripheral cholinergic toxicity thereby improving therapeutic safety. ? ? ?
| Hartmann, Joachim; Kiewert, Cornelia; Duysen, Ellen G et al. (2008) Choline availability and acetylcholine synthesis in the hippocampus of acetylcholinesterase-deficient mice. Neurochem Int 52:972-8 |
| Hartmann, Joachim; Kiewert, Cornelia; Duysen, Ellen G et al. (2007) Excessive hippocampal acetylcholine levels in acetylcholinesterase-deficient mice are moderated by butyrylcholinesterase activity. J Neurochem 100:1421-9 |
