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|Evaluation of Nicotinic Acetylcholine Receptors in Learning and Memory Using Mouse Model of Alzheimer’s Disease
|National University of Sciences & Technology (NUST) Islamabad, Pakistan
|Background: Aluminum (Al) is known to be associated with etiology of different neurodegenerative disorders especially of Alzheimer’s disease (AD) and is known to produce AD like symptoms. It is widely reported that Al affects muscarinic acetylcholine receptors but limited data is available for its effects on nicotinic acetylcholine receptors (nAChRs). The aim of this study was to determine that how Al affects hippocampus, amygdala and cortex dependent learning and memory functions and expression of nAChRs and choline acetyltransferase (ChAT) genes. Effect of Al on cholinergic biomarkers i.e. free choline and acetylcholine (Ach) level were also investigated. Moreover acute effects of Al on nAChRs-mediated modulation of persistent gamma oscillations in hippocampus was also studied. Methods: In order to develop the AD mouse model, AlCl3.6H2O (250 mg/kg) was administered to mice in drinking water 42 days. After completion of Al treatment the learning and memory deficits were assessed via different behavior tests. nAChRs gene expression was determined via RT-PCR in cortex, hippocampus and amygdala. Inductively coupled plasma atomic emission spectrometry (ICP-AES) was used to measure Al accumulation in brain. To determine how Al affects gamma oscillations, field potential recordings were performed in CA3 area of acute hippocampal slices. Results: The results of this study demonstrate that oral Al ingestion caused high accumulation of Al in brain leading to neuropathological changes that suppressed expression of nAChR genes and caused neurodegeneration. Longer in-vitro Al exposure caused permanent changes in hippocampal oscillogenic circuitry and changed its sensitivity to nAChR-modulation, leading to deficits in memory and learning in AD mouse model. Moreover in spite of normal free choline availability Abstract xix Ach synthesis was reduced as a result of oral Al exposure. The reduced Ach synthesis is caused by impaired recycling of Ach due to lower expression of ChAT gene. The reduced Ach level causes deficits in cholinergic neurotransmission which leads to memory and cognitive deficits. Moreover, hippocampus is the most affected brain part after Al intoxication. This study suggests that interference with cholinergic neurotransmission can be the underlying mechanism through which Al causes memory and learning deficits and contributes to neuropathological changes leading to AD.
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|PhD Thesis of All Public / Private Sector Universities / DAIs.
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