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

Abstract

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 beta (Abeta) is the major constituent of NPs and plays a causative role in the pathogenesis of AD. Increasing evidence suggests that the interactions between Abeta 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 Abeta on the cholinergic transmission, especially on neuronal nAChRs and the possible interactive mechanisms among Abeta 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 alpha7 nAChR subunits, along with significant decreases in the levels of alpha7 and alpha4 nAChR subunits on neurons, were detected in both APPswe and sporadic AD brains. The increased expression of alpha7 nAChRs on astrocytes and the decreased expressions of alpha7, alpha4 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 alpha7 nAChRs were positively correlated with the extent of neuropathological alternations. Furthermore, the astrocytic alpha7 nAChRs were morphological associated with amyloid plaques. The elevated expression of astrocytic alpha7 nAChR may participate in the Abeta cascade and the formation of NPs. Abeta-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 Abeta may be involved in the deficits in nAChRs in the PC12 cells. Similarly, a correlation between increased lipid peroxidation and the loss of alpha4 nAChR subunit was detected in AD brain. These findings suggested that lipid peroxidation stimulated by Abeta might be a mechanism for the loss of neuronal nAChRs in AD brain.

The possible interactions among Abeta, 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 Abeta 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 Abeta in vivo. The increased expression of the alpha7 nAChRs and astrocytes in the brain of these mice probably participate in the Abeta cascade and the formation of amyloid plaques. The developmental expression of different nAChRs were investigated in the brains of the alpha7 deficient (alpha7 -/-), alpha7 heterozygous null (alpha7 +/-) and alpha7 wild-type (alpha7 +/+) mice during the postnatal developmental period. Significant increases of the alpha4 and alpha3 nAChR subunits in binding, protein and mRNA levels were detected in the brains of alpha7 -/- and alpha7 +/- mice compared to alpha7 +/+ mice. The increased number of alpha4, alpha3-containing nAChRs, co-assembled with the alpha5 nAChR subunit, may compensate for the lack of or decrease in alpha7 nAChR and contribute to the normal brain development of alpha7 -/- and alpha7 +/- 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 Abeta-induced lipid peroxidation was suggested as a possible mechanism of the deficits of neuronal nAChRs in AD brain. The selective increase of astrocytic alpha7 nAChRs and its morphological association with amyloid plaques might suggest that the astrocytic alpha7 nAChRs are involved in the Abeta cascade and the formation of NPs in AD brain. Based on the possible interaction between Abeta process and nAChRs, especially the alpha7 nAChRs, the alpha7 nAChRs might be a promising target for neuroprotective therapy in AD.