Interactions between Neuronal Nicotinic Acetylcholine Receptors, N-Methyl-D-Aspartate Receptors and β-amyloid in the Brain of Genetically Modified Mice - Implications for Alzheimer’s disease

The amyloid hypothesis is one of the leading theories in the search for the cause of Alzheimer’s disease (AD) and is based on the theory that hyperproduction and accumulation of amyloid β-peptide (Aβ) in the brain triggers the disruption of neuronal and synaptic function, thereby ultimately leading to neurodegeneration and dementia. Some of the crucial questions are if Aβ has a neuronal function in the brain and how it interacts with the neurotransmitter system in AD. The cholinergic α7 neuronal nicotinic receptors (nAChRs) have been suggested to have a close interaction with Aβ. The aim of this thesis has been to investigate the potential neuropathological effect of Aβ on the α7 nAChRs, the N-Methyl-D-Aspartate (NMDA) receptors and their possible interactions, which may play an important role in understanding the cognitive and neuropathological mechanisms seen in AD. To study the effect of Aβ on α7 nAChRs, the PC12 cell line and transgenic mice models (APPswe and APP/PS1) were used. In order to study the interaction between Aβ, α7 nAChRs and NMDA receptors, the APPswe transgenic mouse model was used. It was found that oligomeric Aβ could reduce the number of α7 nAChRs in the PC12 cell line, consistent with the observation in the human AD patients. In the APPswe transgenic mice, a biphasic effect on the α7 nAChRs was found, with a decrease in very young mice followed by an increase at 10 months. A persistent increase in NMDA receptors in cortex and hippocampus of APPswe transgenic mice was observed. The up-regulation of the NMDA receptors in young mice might reflect initial changes in response to the early, high levels of soluble Aβ observed, while the up-regulation at older ages might be due to more chronic exposure of Aβ. The effect of galantamine, memantine and nicotine treatment on the neuropathological changes in the brain, with special focus on Aβ, α7 nAChRs and NMDA receptors, were investigated in APPswe transgenic mice. Subchronic treatment (10 days) with nicotine (0.45 mg/kg/day x 2) reduced the insoluble Aβ1-40 and Aβ1-42 levels by 46 % and 66 % respectively, while the intracellular Aβ levels remained unchanged. This also resulted in less GFAP (glial fibrillary acidic protein) immunoreactive astrocytes around the plaques and increased levels of both synaptophysin and the number of α7 nAChRs in the cortex of APPswe transgenic mice. Galantamine treatment (2 mg/kg/day x 2) caused a 2-fold increase in cortical synaptophysin levels in the APPswe mice. Memantine treatment (10 mg/kg/day x 2) reduced the total cortical levels of membrane-bound APP by 45 % and 55 % in transgenic and non-transgenic mice respectively, which eventually may decrease the level of Aß. The α7 nAChRs and NMDA receptors are important in mediating synaptic plasticity in the brain. A persistent exposure to Aβ in the brain of APPswe transgenic mice causes an increase in both the α7 nAChRs and the NMDA receptors. Treatment with galantamine, memantine or nicotine showed different effects on Aß processes, α7 nAChRs and NMDA receptors in APPswe mice. These different effects might have therapeutic relevance and this knowledge might be applicable to the development of new effective therapeutic strategies in AD. LIST OF PUBLICATIONS This thesis is based on the following papers, which will be referred to in the text by their roman numbers: I. Guan ZZ, Miao H, Tian JY, Unger C, Nordberg A and Zhang X Suppressed expression of nicotinic acetylcholine receptors by nanomolar beta-amyloid peptides in PC12 cells. Journal of Neural Transmission, 2001, 108(12), 1417-1433 II. Marutle A, Unger C, Hellström-Lindahl E, Wang J, Puoliväli J, Tanila H, Nordberg A and Zhang X Elevated levels of Abeta1-40 and Abeta1-42 do not alter the binding sites of nicotinic receptor subtypes in the brain of APPswe and PS1 double transgenic mice. Neuroscience Letters, 2002, 328(3), 269-72 III. Unger C, Hedberg MM, Mustafiz T, Svedberg MM and Nordberg A Early Changes in Aβ Levels in the brain of APPswe transgenic mice Implication on synaptic density, α7 neuronal nicotinic acetylcholineand NMethyl-D-Aspartate receptor levels Molecular and Cellular Neuroscience, 2005, 30 (2), 218-227 IV. Unger C, Svedberg MM, Schutte M, Bednar I and Nordberg A Effect of memantine on the alpha7 neuronal nicotinic receptors, synaptophysinand low molecular weight MAP-2 levels in the brain of transgenic mice over-expressing human acetylcholinesterase. Journal of Neural Transmission, 2005, 112(2), 255-68 V. Unger C, Svedberg MM, Yu W-F, Hedberg MM and Nordberg A Effect of Subchronic Treatment of Memantine, Galantamine and Nicotine in the Brain of APPswe Transgenic Mice Submitted to Journal of Pharmacology and Experimental Therapeutics All previously published papers were reproduced with permission from the publisher