Neuronal nicotinic receptor subtypes in normal ageing, Alzheimer's disease and schizophrenia : influences of neuropathological mechanisms as studied in human autopsy brain and transgenic mice

Abstract

Neuronal nicotinic acetylcholine receptors (nAChRs) are transmitter-gated ion channel receptors which are widely distributed in the brain. They mediate the effects of several neurotransmitters including ACh, DA, 5-HT and NA and are important for many normal physiological functions in the brain and are also implicated in a number of CNS disorders, such as AD, PD, schizophrenia, Tourette's syndrome and familial epilepsy. The overall aim of this thesis was to characterise changes in various nAChR subtypes during normal ageing, Alzheimer's disease (AD) and schizophrenia in postmortem human brain, and to investigate the neuropathological influences of characteristic AD lesions, eg. beta-amyloid (A-beta) deposition on nAChRs in the brains of two different transgenic mice models related to AD.

Selective losses of particularly alpha3-containing nAChRs, but also alpha-4-beta-2 nAChRs were observed in different human autopsy brain regions at normal ageing. A comparison of nAChR deficits in cortical regions of sporadic AD cases versus those in subjects with familial Swedish APP 670/671 encoded mutation AD (FAD APP 670/671) showed that mutation carriers had similar deficits in nAChRs. This indicated that pronounced disturbances in APP metabolism result in similar neurotransmitter deficits as in cases where probably the mismetabolism is less pronounced. Investigation of the relationship between nAChR loss and neuropathological features i.e. deposition of amyloid plaques and neurofibrillary tangles in the cerebral cortex of FAD APP 670/671 carriers revealed no strict correlation.

Two recently developed transgenic mice models, the APPSWE mouse harboring the 670/671 Swedish double mutation and the APPSWE /PS1 mouse expressing both the 670/671 Swedish double mutation and a FAD human PSI mutation, were used to study whether there was a potential link between A-beta production and accumulation and deficits in nAChRs as observed in the AD brain.

Behavioural studies in the APPSWE mice revealed impairment in locomotion at 3 months, and impaired performance in water T-maze spatial working memory tasks at 10 months. Significant increases in alpha-7 nAChRs were observed at 4 months in various brain regions of APPSWE mice, preceding disturbances in learning and memory and A-beta pathology. This upregulation persisted at 17-19 months. Increases in alpha-4-beta-2 nAChRs were observed at 18 months, when the APPSWE mice showed heavy A-beta pathology. No changes in muscarinic receptors were detected. The upregulation of nAChRs in these transgenic mice probably reflect compensatory mechanisms in response to A-beta burden. No alterations of the binding sites of nAChR subtypes were observed in APPSWE /PS 1 transgenic mice, despite elevated levels of A-beta 1-40 and A-beta 1-42. These results indicate different effects on nAChRs between the two transgenic mice models. Moreover, the discrepancy in nAChR changes in transgenic mice brain and the AD brain provide evidence that these transgenic animals are not representative models for the neurodegenerative processes occurring in the human brain.

We investigated changes in nAChRs in schizophrenia brain, and found selective reductions in 0C7 nAChRs in the cingulate cortex. In addition, a selective increase in high-affinity alpha-4-beta-2 nAChRs was also detected in the same brain region, probably reflecting the heavy tobacco use among schizophrenia patients. The lack of a loss of alpha-4-beta-2 nAChRs in schizophrenia is opposite to the marked loss of this receptor subtype observed in cortical regions and hippocampus in AD. It appears that the alpha-7 nAChRs are more vulnerable in schizoprenia compared to AD patients. These collective findings suggest that different nAChR subtypes are affected in the pathological cascades for these two diseases.

In conclusion, these studies show that selective changes in different nAChR subtypes occur in diverse brain regions during various physiological and neurodegenerative conditions. Deducing changes in various subtypes in disease states from the normal may hopefully give us a further understanding of the function(s) of these receptor subtypes in specific pathways of the brain. There is a future challenge whether compounds can be developed which are selective in producing improvement in cognition and behavioural and attentional deficits associated with several CNS disorders without significant side effects.