|dc.description.abstract||In the current thesis, the function of the septohippocampal cholinergic nervous system was investigated in transgenic mouse models pertinent to Alzheimer’s disease. First, a transgenic model of increased amyloid formation and deposition was investigated to see whether a cholinergic deficit, as observed in the human disease, is present in those animals. These mice express both a mutated human amyloid precursor protein and human presenilin-1 and generate amyloid peptide and neuritic plaques in an age-dependent manner. High-affinity choline uptake (HACU) into corticohippocampal synaptosomes showed no difference between double mutant transgenic mice and controls, indicating unchanged turnover of the neurotransmitter, acetylcholine (ACh). Extracellular levels of ACh, measured in the dorsal hippocampus using microdialysis, were not significantly different between groups. The response of these levels to stimulation with either scopolamine or by exposure of animals to a novel environment was also unchanged between mutant mice and controls, indicating retained capability of the central cholinergic system to respond to different challenges. In conclusion, this study demonstrated that amyloid pathology can occur without compromising hippocampal cholinergic neurotransmission.
For the second part of this thesis, mice deficient for the enzyme acetylcholinesterase (AChE) were obtained; they serve as a model of the predominant treatment used in Alzheimer’s disease, inhibition of AChE. Microdialysis in dorsal hippocampus revealed vastly elevated baseline levels of ACh, whereas baseline levels of Ch were reduced. Selective inhibition of butyrylcholinesterase (BChE) further increased these levels of ACh in AChE-deficient, but not in control mice. This observation, for the first time, provides clear evidence that BChE can hydrolyze ACh in the brain of a living organism. Elevated levels of ACh were sensitive to the absence of calcium and to tetrodotoxin, confirming their neuronal origin. A compensatory increase in HACU was found, indicating increased transmitter turnover. Furthermore, it was demonstrated that extracellular levels of Ch become rate-limiting for ACh release in the absence of AChE. Finally, a relative failure of presynaptic negative autofeedback receptors was observed. The conclusion is reached that, in the absence of AChE, ACh hydrolysis is maintained to a considerable degree by BChE. Moreover, compensatory changes in the absence of AChE include upregulation of HACU and functional loss of inhibitory autofeedback receptors.
In summary, both mouse models demonstrate that central cholinergic systems can respond to a wide range of challenges with a remarkable degree of adaptation.||