Faculty of Pharmacy with Subfaculty of Laboratory Medicine, Medical University of Gdańsk, 80-416 Gdańsk, Poland.
Department of Biology and Medical Genetics, Medical University of Gdańsk, 80-211 Gdańsk, Poland.
Biomolecules. 2019 Oct 9;9(10):592. doi: 10.3390/biom9100592.
Late-onset Alzheimer's disease (AD) is clinically characterized by a progressive decline of memory and other cognitive functions leading to the loss of the ability to perform everyday activities. Only a few drugs have been approved to treat AD dementia over the past century since the first AD patient was diagnosed. Drugs increasing the availability of neurotransmitters at synapses in the brain are used clinically in the treatment of AD dementia, and cholinesterase inhibitors (ChEIs) are the mainstay of the therapy. A detrimental effect on cognitive function has been reported in patients with pharmacological inhibition of acetylcholinesterase (AChE) by ChEIs and reduced butyrylcholinesterase (BChE) activity due to the single nucleotide polymorphisms. The BChE K-variant (rs1803274), the most common genetic variant of the gene, was thought to reduce enzyme activity reflecting the lower clinical response to rivastigmine in AD patients. During ChEIs therapy, patients carrying reduced-activity BChE do not present such improved attention like patients with the wild-type enzyme. On the other hand, alterations in the gene causing enzyme activity reduction may delay AD onset in patients at risk by preserving the level of cortical acetylcholine (ACh). Based on our previous results, we conclude that SNPs localized outside of the coding sequence, in 5'UTR (rs1126680) and/or intron 2 (rs55781031) of the gene, but not solely K-variant alteration (p.A539T) itself, are responsible for reduced enzyme activity. Therefore, we suspect that not BChE-K itself, but these coexisting SNPs (rs1126680 and rs55781031), could be associated with deleterious changes in cognitive decline in patients treated with ChEIs. Based on the results, we suggest that SNPs (rs1126680) and/or (rs55781031) genotyping should be performed to identify subjects at risk for lowered efficacy ChEIs therapy, and such patients should be treated with a lower rivastigmine dosage. Finally, our sequence analysis of the N-terminal end of N-BChE revealed evolutionarily conserved amino acid residues that can be involved in disulfide bond formation and anchoring of N-BChE in the cell membrane.
晚发性阿尔茨海默病（AD）的临床特征是记忆和其他认知功能逐渐下降，导致无法进行日常活动。自第一个 AD 患者被诊断以来，在过去的一个世纪里，只有少数几种药物被批准用于治疗 AD 痴呆。临床上用于治疗 AD 痴呆的药物是增加突触中神经递质可用性的药物，而胆碱酯酶抑制剂（ChEIs）是治疗的主要方法。由于单核苷酸多态性，ChEIs 对乙酰胆碱酯酶（AChE）的药理学抑制以及降低的丁酰胆碱酯酶（BChE）活性对认知功能有不利影响。BChE K 变体（rs1803274）是 基因最常见的遗传变体，被认为降低了反映 AD 患者对利斯的明临床反应较低的酶活性。在 ChEIs 治疗期间，携带活性降低的 BChE 的患者与具有野生型酶的患者不同，不会出现注意力改善的情况。另一方面，导致酶活性降低的 基因改变可能通过维持皮质乙酰胆碱（ACh）水平来延迟有风险的患者的 AD 发作。基于我们之前的结果，我们得出结论，位于编码序列之外的 5'UTR（rs1126680）和/或内含子 2（rs55781031）中的 SNPs，但不仅是 K 变体改变（p.A539T）本身，负责降低酶活性。因此，我们怀疑不是 BChE-K 本身，而是这些共存的 SNPs（rs1126680 和 rs55781031）可能与接受 ChEIs 治疗的患者认知能力下降的有害变化有关。基于这些结果，我们建议进行 SNPs（rs1126680）和/或（rs55781031）基因分型，以识别 ChEIs 治疗效果降低的风险患者，并且此类患者应使用较低剂量的利斯的明进行治疗。最后，我们对 N-BChE 的 N 端进行序列分析，发现了进化上保守的氨基酸残基，这些残基可能参与二硫键形成和 N-BChE 在细胞膜中的锚定。
