Laboratory of Neurobiology and Molecular Psychiatry, Department of Biochemistry, Faculty of Science, Masaryk University, Kotlářská 2, 611 37, Brno, Czech Republic.
Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
J Biomed Sci. 2018 May 14;25(1):41. doi: 10.1186/s12929-018-0444-2.
Cholinergic hypothesis of Alzheimer's disease (AD) is based on the findings that a reduced and/or perturbed cholinergic activity in the central nervous system correlates with cognitive decline in patients with Alzheimer's disease. The hypothesis resulted in the development of centrally-acting agents potentiating cholinergic neurotransmission; these drugs, however, only slowed down the cognitive decline and could not prevent it. Consequently, the perturbation of the central cholinergic signalling has been accepted as a part of the Alzheimer's aetiology but not necessarily the primary cause of the disease. In the present study we have focused on the rs3810950 polymorphism of ChAT (choline acetyltransferase) gene that has not been studied in Czech population before.
We carried out an association study to test for a relationship between the rs3810950 polymorphism and Alzheimer's disease in a group of 1186 persons; 759 patients with Alzheimer's disease and 427 control subjects. Furthermore, we performed molecular modelling of the terminal domain (1st-126th amino acid residue) of one of the ChAT isoforms (M) to visualise in silico whether the rs3810950 polymorphism (A120T) can change any features of the tertiary structure of the protein which would have a potential to alter its function.
The AA genotype of CHAT was associated with a 1.25 times higher risk of AD (p < 0.002) thus demonstrating that the rs3810950 polymorphism can have a modest but statistically significant effect on the risk of AD in the Czech population. Furthermore, the molecular modelling indicated that the polymorphism is likely to be associated with significant variations in the tertiary structure of the protein molecule which may impact its enzyme activity.
Our findings are consistent with the results of the meta-analytical studies of the relationship between rs3810950 polymorphism and AD and provide further material evidence for a direct (primary) involvement of cholinergic mechanisms in the etiopathogenesis of AD, particularly as a factor in cognitive decline and perturbed conscious awareness commonly observed in patients with AD.
阿尔茨海默病（AD）的胆碱能假说基于这样的发现，即中枢神经系统中胆碱能活性的降低和/或紊乱与 AD 患者的认知能力下降相关。该假说导致了中枢作用增强胆碱能神经传递的药物的发展；然而，这些药物仅减缓了认知能力下降的速度，而不能预防其发生。因此，中枢胆碱能信号的紊乱被认为是 AD 发病机制的一部分，但不一定是疾病的主要原因。在本研究中，我们专注于 ChAT（胆碱乙酰转移酶）基因的 rs3810950 多态性，该多态性以前在捷克人群中尚未进行过研究。
我们进行了一项关联研究，以检验 rs3810950 多态性与 1186 名患者（759 名 AD 患者和 427 名对照组）中的 AD 之间的关系。此外，我们对其中一种 ChAT 同工型（M）的末端结构域（第 1 位到第 126 位氨基酸残基）进行了分子建模，以可视化 rs3810950 多态性（A120T）是否可以改变蛋白质三级结构的任何特征，这些特征可能会改变其功能。
CHAT 的 AA 基因型与 AD 的风险增加 1.25 倍相关（p<0.002），这表明 rs3810950 多态性在捷克人群中对 AD 的风险有适度但统计学显著的影响。此外，分子建模表明，该多态性可能与蛋白质分子三级结构的显著变化相关，这可能影响其酶活性。
我们的发现与 rs3810950 多态性与 AD 之间的荟萃分析研究结果一致，并为胆碱能机制直接（主要）参与 AD 的发病机制提供了进一步的物质证据，特别是作为 AD 患者常见的认知能力下降和意识紊乱的一个因素。
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