Interactions between neuronal nicotinic acetylcholine receptors, N-methyl-aspartate receptors and beta-amyloid in the brain of genetically modified mice : implications for Alheimer'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 betapeptide (Abeta) 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 Abeta has a neuronal function in the brain and how it interacts with the neurotransmitter system in AD. The cholinergic W neuronal nicotinic receptors (nAChRs) have been suggested to have a close interaction with Abeta.

The aim of this thesis has been to investigate the potential neuropathological effect of Abeta on the alpha7 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 Abeta on alpha7 nAChRs, the PC12 cell line and transgenic mice models (APPswe and APP/PS1) were used. In order to study the interaction between Abeta, alpha7 nAChRs and NMDA receptors, the APPswe transgenic mouse model was used. It was found that oligomeric Abeta could reduce the number of alpha7 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 alpha7 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 Abeta observed, while the upregulation at older ages might be due to more chronic exposure of Abeta.

The effect of galantamine, memantine and nicotine treatment on the neuropathological changes in the brain, with special focus on Abeta, alpha7 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 API-40 and API-42 levels by 46 % and 66 % respectively, while the intracellular Abeta 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 alpha7 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 AB. The alpha7 nAChRs and NMDA receptors are important in mediating synaptic plasticity in the brain. A persistent exposure to Abeta in the brain of APPswe transgenic mice causes an increase in both the alpha7 nAChRs and the NMDA receptors. Treatment with galantamine, memantine or nicotine showed different effects on AB processes, alpha7 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 scientific papers

I. Guan ZZ, Miao H, Tian JY, Unger C, Nordberg A, Zhang X (2001). Suppressed expression of nicotinic acetylcholine receptors by nanomolar beta-amyloid peptides in PC12 cells. J Neural Transm. 108(12): 1417-33.
https://doi.org/10.1007/s007020100017

II. Marutle A, Unger C, Hellstrom-Lindahl E, Wang J, Puolivali J, Tanila H, Nordberg A, Zhang X (2002). 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. Neurosci Lett. 328(3): 269-72.
https://doi.org/10.1016/S0304-3940(02)00546-3

III. Unger C, Hedberg MM, Mustafiz T, Svedberg MM, Nordberg A (2005). Early changes in Abeta levels in the brain of APPswe transgenic mice--implication on synaptic density, alpha7 neuronal nicotinic acetylcholine- and N-methyl-D-aspartate receptor levels. Mol Cell Neurosci. 30(2): 218-27.
https://doi.org/10.1016/j.mcn.2005.07.012

IV. Unger C, Svedberg MM, Schutte M, Bednar I, Nordberg A (2005). Effect of memantine on the alpha 7 neuronal nicotinic receptors, synaptophysin- and low molecular weight MAP-2 levels in the brain of transgenic mice over-expressing human acetylcholinesterase. J Neural Transm. 112(2): 255-68.
https://doi.org/10.1007/s00702-004-0183-2

V. Unger C, Svedberg MM, Yu WF, Hedberg MM, Nordberg A (2005). Effect of subchronic treatment of memantine, galantamine and nicotine in the brain of APPswe transgenic mice. [Submitted]