Šerý Omar, Sheardová Kateřina, Dziedzinska Radka, Zeman Tomáš, Vyhnálek Martin, Marková Hana, Laczó Jan, Lochman Jan, Vrzalová Kamila, Balcar Vladimir J, Hort Jakub
Laboratory of Neurobiology and Molecular Psychiatry, Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czech Republic.
Laboratory of Neurobiology and Pathological Physiology, Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic.
J Gerontol A Biol Sci Med Sci. 2025 May 5;80(6). doi: 10.1093/gerona/glaf055.
The ABCB1 gene, encoding the ATP-dependent translocase ABCB1, plays a crucial role in the clearance of amyloid-beta (Aβ) peptides and the transport of cholesterol, implicating it in the pathogenesis of Alzheimer's disease. The study aims to investigate the association between polymorphisms in the ABCB1 gene and cognitive decline in individuals with mild cognitive impairment (MCI), particularly focusing on language function. A longitudinal cohort study involving 1 005 participants from the Czech Brain Aging Study was conducted. Participants included individuals with Alzheimer's disease, amnestic MCI, non-amnestic MCI, subjective cognitive decline, and healthy controls. Next-generation sequencing was utilized to analyze the entire ABCB1 gene. Cognitive performance was assessed using a comprehensive battery of neuropsychological tests, including the Boston Naming Test and the semantic verbal fluency test. Ten ABCB1 polymorphisms (rs55912869, rs56243536, rs10225473, rs10274587, rs2235040, rs12720067, rs12334183, rs10260862, rs201620488, and rs28718458) were significantly associated with cognitive performance, particularly in language decline among amnestic MCI patients. In silico analyses revealed that some of these polymorphisms may affect the binding sites for transcription factors (HNF-3alpha, C/EBPβ, GR-alpha) and the generation of novel exonic splicing enhancers. Additionally, polymorphism rs55912869 was identified as a potential binding site for the microRNA hsa-mir-3163. Our findings highlight the significant role of ABCB1 polymorphisms in cognitive decline, particularly in language function, among individuals with amnestic MCI. These polymorphisms may influence gene expression and function through interactions with miRNAs, transcription factors, and alternative splicing mechanisms.
编码ATP依赖性转运蛋白ABCB1的ABCB1基因在β淀粉样蛋白（Aβ）肽的清除和胆固醇的转运中起关键作用，这表明它与阿尔茨海默病的发病机制有关。该研究旨在调查ABCB1基因多态性与轻度认知障碍（MCI）个体认知衰退之间的关联，尤其关注语言功能。对来自捷克脑老化研究的1005名参与者进行了一项纵向队列研究。参与者包括阿尔茨海默病患者、遗忘型MCI患者、非遗忘型MCI患者、主观认知衰退者和健康对照者。利用下一代测序技术分析整个ABCB1基因。使用一系列全面的神经心理学测试评估认知表现，包括波士顿命名测试和语义言语流畅性测试。10个ABCB1多态性位点（rs55912869、rs56243536、rs10225473、rs10274587、rs2235040、rs12720067、rs12334183、rs10260862、rs201620488和rs28718458）与认知表现显著相关，尤其是在遗忘型MCI患者的语言衰退方面。计算机分析表明，其中一些多态性可能会影响转录因子（HNF-3α、C/EBPβ、GR-α）的结合位点以及新型外显子剪接增强子的产生。此外，多态性位点rs55912869被确定为微小RNA hsa-mir-3163的潜在结合位点。我们的研究结果突出了ABCB1多态性在遗忘型MCI个体认知衰退，尤其是语言功能衰退中的重要作用。这些多态性可能通过与微小RNA、转录因子和可变剪接机制的相互作用影响基因表达和功能。
