Beta-amyloid processing and alpha7 neuronal nicotinic acetylcholine receptors in Alzheimer s disease-related mouse models : Interactive mechanisms with focus on new drug targets

Abstract: Accumulation of beta-amyloid (Abeta), neuronal loss and changes in neurotransmitter systems, in particular the cholinergic system, are consistent features of Alzheimer s disease (AD). Abeta is thought to play a critical role in the pathogenesis of AD and it has therefore become a target of interest as regards a therapeutic approach. The aim of this work was to investigate how different Abeta peptides influence neurotransmission in the brains of AD-related mouse models, as well as to evaluate how drugs, acting via the cholinergic and glutamatergic neurotransmitter systems, affect these processes. Three different transgenic mouse models were utilized: APPswe, hAChE-Tg//APPswe and 3xTg-AD mice, which revealed diverse brain Abeta pathologies. The hAChE-Tg//APPswe mice exhibited accelerated plaque pathology and showed, even at early ages, increased levels of insoluble Abeta in their brains compared with age-matched APPswe mice, whereas the latter expressed increased soluble Abeta. The 3xTg-AD mice showed no extracellular Abeta plaques, while intraneuronal APP/Abeta immunostaining was evident in the cortex and the hippocampus. Whereas APPswe mice showed a more pronounced Abeta pathology, with high Abeta levels both in the cortex and the hippocampus, the 3xTg-AD mice showed detectable Abeta peptides solely in the hippocampus. A biphasic effect was found on cortical alpha7 neuronal nicotinic acetylcholine receptors (nAChRs) in APPswe mice, with an initial decrease at early ages, followed by an increase at later ages, while the N-methyl-D-aspartate (NMDA) receptors showed a persistent increase from a young age. The increased receptor levels probably reflect compensatory mechanisms in response to a high Abeta burden. No changes were found in alpha7 nAChRs in hAChE-Tg//APPswe mice or 3xTg-AD mice. At a very early age, the APPswe mice expressed increased cortical synaptophysin levels, followed by a persistent decrease. In 3xTg-AD mice, the observed reduction in cortical synaptophysin might be ascribed to the presence of intraneuronal Abeta. The choice of transgenic mouse model, as well as the stage of Abeta pathology, was shown to strongly affect the outcome of drug treatment. While decreasing cortical insoluble Abeta1−40 and Abeta1−42 in APPswe mice, L(-)-nicotine increased cortical insoluble Abeta1 40 and soluble Abeta1 42 (both enantiomers) in hAChE-Tg//APPswe mice. However, in both mouse models nicotine reduced glial fibrillary acidic protein (GFAP) immunoreactive astrocytes. In APPswe mice, L(-)-nicotine increased hippocampal and cortical alpha7 nAChRs, while D(+)-nicotine treatment resulted in an increase in these receptors in hAChE-Tg//APPswe mice. Huprine X decreased hippocampal insoluble Abeta1−40, the levels of alpha7 nAChRs in the caudate nucleus, and increased cortical synaptophysin levels in 3xTg-AD mice, while only increasing the levels of alpha7 nAChRs in the hippocampi of APPswe mice. Treatment with the current AD drug galantamine increased cortical synaptophysin levels and affected the NMDA receptors, indicating plastic changes in the brain, while memantine reduced cortical levels of membrane-bound amyloid precursor protein (APP), which eventually may decrease Abeta levels. In conclusion, the diverse forms of Abeta displayed in the mouse models studied gave rise to differences in brain neuropathology, with diverging results regarding synapses and neuronal receptors as well as the outcome of drug treatment. The results in this work clearly highlight the fact that the choice of transgenic mouse model, as well as the stage of Abeta pathology, contribute importantly to the outcome of drug treatment. This emphasizes the importance of using different transgenic mouse models for evaluating the effects of new drug candidates for this devastating disease.