Clarimón Jordi, Bertranpetit Jaume, Calafell Francesc, Boada Mercè, Tàrraga Lluís, Comas David
Unitat de Biologia Evolutiva, Facultat de Ciències de la Salut i de la Vida, Universitat Pompeu Fabra, Doctor Aiguader 80, 08003 Barcelona, Spain.
J Neurol. 2003 Aug;250(8):956-61. doi: 10.1007/s00415-003-1127-8.
Amyloid beta-peptide (Abeta) biosynthesis, aggregation and degradation constitute three important steps to consider in the study of pathological mechanisms involved in Alzheimer's disease (AD). Several proteins have been suggested as involved in each of these processes: proteolytic cleavage of the amyloid precursor protein by the beta-site APP cleaving enzyme (BACE), increased amyloid fibril formation by the activity of the acetylcholinesterase (ACHE gene), and degradation of Abeta aggregates by the plasmin system have been exhaustively documented.
A case-control design was used to evaluate the possible association between candidate genes involved in these three processes and AD. We analysed three polymorphisms located at the BACE1 gene, one polymorphism at the ACHE gene, and two variants located at the tissue plasminogen activator and plasminogen activator inhibitor-1 (genes TPA and PAI- 1, respectively), both part of the plasmin system.
We found an association between BACE1 exon 5 GG genotype and AD (age-and gender-adjusted odds ratio = 2.14, P =0.014). Although a similar association was reported previously by Nowotny and collaborators only in subjects carrying the epsilon4-allele of the apolipoprotein E gene (APOE), we did not detect this effect. However,when we combined our results with those previously reported, a clear increase of the risk to develop AD appeared in subjects carrying both the BACE1 exon 5 GG genotype and the APOE epsilon4-allele (crude OR = 2.2, P = 0.004).
These data suggest a possible genetic relation between BACE1 and AD.
淀粉样β肽（Aβ）的生物合成、聚集和降解是阿尔茨海默病（AD）病理机制研究中需要考虑的三个重要步骤。已有多种蛋白质被认为参与了这些过程：β位点淀粉样前体蛋白裂解酶（BACE）对淀粉样前体蛋白的蛋白水解切割、乙酰胆碱酯酶（ACHE基因）活性增加导致淀粉样纤维形成增加，以及纤溶酶系统对Aβ聚集体的降解，这些都有详尽的记录。
采用病例对照设计来评估参与这三个过程的候选基因与AD之间可能存在的关联。我们分析了位于BACE1基因的三个多态性、位于ACHE基因的一个多态性，以及位于组织纤溶酶原激活物和纤溶酶原激活物抑制剂-1（分别为TPA和PAI-1基因）的两个变体，它们都是纤溶酶系统的一部分。
我们发现BACE1外显子5的GG基因型与AD之间存在关联（年龄和性别校正比值比=2.14，P=0.014）。尽管诺沃特尼及其合作者之前仅在携带载脂蛋白E基因（APOE）ε4等位基因的受试者中报道过类似关联，但我们并未检测到这种效应。然而，当我们将我们的结果与之前报道的结果相结合时，同时携带BACE1外显子5 GG基因型和APOE ε4等位基因的受试者患AD的风险明显增加（粗比值比=2.2，P=0.004）。
这些数据表明BACE1与AD之间可能存在遗传关系。
