Interactive mechanism between beta-amyloid process, alfa7 nicotinic receptor, glial cell activation and oxidative stress in Alzheimer's disease

Alzheimer’s disease (AD) is the most common form of dementia with pathological features including the accumulation of neuritic plaques (NPs) and neurofibrillary tangles (NFTs). These degenerative processes are also accompanied by impaired cholinergic transmission, oxidative stress, activated glia and inflammation reaction. Amyloid β (Aβ) is the major constituent of NPs and plays a causative role in the pathogenesis of AD. Increasing evidence suggests that the interactions between Aβ process and nicotinic receptors (nAChRs) may play an important role in the pathogenesis of AD. The main purposes of this thesis were to investigate the potential neuropathological effects of Aβ on the cholinergic transmission, especially on neuronal nAChRs and the possible interactive mechanisms among Aβ process, nAChRs, and activated glia in the pathogenesis of AD. The distribution changes of different nAChRs on astrocytes and neurons were investigated in the brains of subjects carrying the Swedish APP 670/671 mutation (APPswe) and sporadic AD. Significant increases of astrocytes expressing the α7 nAChR subunits, along with significant decreases in the levels of α7 and α4 nAChR subunits on neurons, were detected in both APPswe and sporadic AD brains. The increased expression of α7 nAChRs on astrocytes and the decreased expressions of α7, α4 nAChR subunits on neurons in the brain of APPswe were more pronounced in comparison to the sporadic AD brain. While the increased expression of astrocytic α7 nAChRs were positively correlated with the extent of neuropathological alternations. Furthermore, the astrocytic α7 nAChRs were morphological associated with amyloid plaques. The elevated expression of astrocytic α7 nAChR may participate in the Aβ cascade and the formation of NPs. Aβ-induced oxidative stress was investigated as a possible mechanism for the deficits of neuronal nAChRs in both AD brains and the PC12 cells. It was found that lipid peroxidation induced directly by Aβ may be involved in the deficits in nAChRs in the PC12 cells. Similarly, a correlation between increased lipid peroxidation and the loss of α4 nAChR subunit was detected in AD brain. These findings suggested that lipid peroxidation stimulated by Aβ might be a mechanism for the loss of neuronal nAChRs in AD brain. The possible interaction s among Aβ, acetylcholinesterase (AChE), activated glia and nAChRs were investigated in the brains of the double transgenic mice carrying the APPswe mutation and overexpressing the human AChE (hAChE-Tg//APPswe mice). Results showed that Aβ deposition occurred more early in the brain of the double transgenic mice compared to the single APPswe mice. These results confirmed that AChE might promote the deposition of Aβ in vivo. The increased expression of the α7 nAChRs and astrocytes in the brain of these mice probably participate in the Aβ cascade and the formation of amyloid plaques. The developmental expression of different nAChRs were investigated in the brains of the α7 deficient (α7 -/-), α7 heterozygous null (α7 +/-) and α7 wild-type (α7 +/+) mice during the postnatal developmental period. Significant increases of the α4 and α3 nAChR subunits in binding, protein and mRNA levels were detected in the brains of α7 -/and α7 +/mice compared to α7 +/+ mice. The increased number of α4, α3-containing nAChRs, co-assembled with the α5 nAChR subunit, may compensate for the lack of or decrease in α7 nAChR and contribute to the normal brain development of α7 -/and α7 +/mice in brain. In conclusion, these studies show that selective changes of nAChR subunits were found between neuron and astrocytes in AD brain. The decreased neuronal nAChRs might reflect the neurodegenerative condition of neurons in AD brain. The Aβ-induced lipid peroxidation was suggested as a possible mechanism of the deficits of neuronal nAChRs in AD brain. The selective increase of astrocytic α7 nAChRs and its morphological association with amyloid plaques might suggest that the astrocytic α7 nAChRs are involved in the Aβ cascade and the formation of NPs in AD brain. Based on the possible interaction between Aβ process and nAChRs, especially the α7 nAChRs, the α7 nAChRs might be a promising target for neuroprotective therapy in AD. LIST OF PUBLICATIONS This thesis is based upon the following publications, which are referred to in the text by their Roman numerals I-V: I. Yu WF*, Guan ZZ*, Bogdanovic N, Nordberg A. (2005) High selective expression of alpha7 nicotinic receptors on astrocytes in the brains of patients with sporadic Alzheimer's disease and patients carrying Swedish APP 670/671 mutation: a possible association with neuritic plaques. Experimental Neurology 192: 215-225. These authors contributed equally to this work II. Guan ZZ, Yu WF, Shan KR, Nordman T, Olsson J, Nordberg A. (2003) Loss of nicotinic receptors induced by beta-amyloid peptides in PC12 cells: possible mechanism involving lipid peroxidation. Journal of Neuroscience Research 71: 397-406. III. Yu WF, Nordberg A, Ravid R, Guan ZZ. (2003) Correlation of oxidative stress and the loss of the nicotinic receptor alpha 4 subunit in the temporal cortex of patients with Alzheimer's disease. Neuroscience Letters 338: 13-16. IV. Svedberg MM, Unger C, Yu WF, Mousavi M, Guan ZZ, Nordberg A. Consequences of increased soluble and insoluble β-amyloid levels at different ages in the brain of transgenic mice overexpressing both human acetylcholinestrase and the APPswe mutation. Submitted. V. Yu WF, Guan ZZ, Nordberg A. Postnatal upregulation of α4 and α3 nicotinic receptor subunits in the brain of α7 nicotinic receptor-deficient mice. Submitted. Reprints were made with permission from the publishers.