Papassotiropoulos A, Bagli M, Feder O, Jessen F, Maier W, Rao M L, Ludwig M, Schwab S G, Heun R
Department of Psychiatry, University of Bonn, Germany.
Neurosci Lett. 1999 Mar 12;262(3):171-4. doi: 10.1016/s0304-3940(99)00071-3.
The beta amyloid peptide derives from its precursor protein via proteolytic cleavage of yet unidentified proteases (beta- and gamma-secretases). Cathepsin D is an intracellular protease with in-vitro beta-secretase-like features. An exonic polymorphism of the cathepsin D gene (alanine to valine transition at position 224, exon 2) has been associated with altered enzyme function. We tested the hypothesis that this polymorphism is associated with an increased risk for Alzheimer's disease in 102 demented patients, 191 healthy subjects, and 160 depressed patients. There was a highly significant overrepresentation of the cathepsin DT allele in demented patients (14.2%) compared to non-demented controls (6.7%, P = 0.0012). Carriers of the cathepsin DT allele had a 2.4-fold increased risk for developing AD than non-carriers. Carriers of the apolipoprotein E epsilon 4 allele had a 4.1 -fold increased risk than non-carriers. The odds ratio for subjects with the apolipoprotein E epsilon 4 and the cathepsin D*T allele was 5.9. Our data suggest that the cathepsin D genotype is strongly associated with the risk for Alzheimer's disease.
β淀粉样肽是通过尚未明确的蛋白酶（β-和γ-分泌酶）对其前体蛋白进行蛋白水解切割而产生的。组织蛋白酶D是一种具有体外β-分泌酶样特征的细胞内蛋白酶。组织蛋白酶D基因的一个外显子多态性（第2外显子第224位由丙氨酸转变为缬氨酸）与酶功能改变有关。我们在102例痴呆患者、191例健康受试者和160例抑郁症患者中检验了这种多态性与阿尔茨海默病风险增加相关的假设。与非痴呆对照组（6.7%，P = 0.0012）相比，痴呆患者中组织蛋白酶DT等位基因的比例显著过高（14.2%）。组织蛋白酶DT等位基因携带者患阿尔茨海默病的风险是非携带者的2.4倍。载脂蛋白Eε4等位基因携带者的风险是非携带者的4.1倍。同时携带载脂蛋白Eε4和组织蛋白酶D*T等位基因的受试者的优势比为5.9。我们的数据表明，组织蛋白酶D基因型与阿尔茨海默病风险密切相关。
