Wollmer M Axel, Streffer Johannes R, Lütjohann Dieter, Tsolaki Magdalini, Iakovidou Vassiliki, Hegi Thomas, Pasch Thomas, Jung Hans H, Bergmann Klaus von, Nitsch Roger M, Hock Christoph, Papassotiropoulos Andreas
Division of Psychiatry Research, University of Zürich, August Forel Street 1, 8008, Zürich, Switzerland.
Neurobiol Aging. 2003 May-Jun;24(3):421-6. doi: 10.1016/s0197-4580(02)00094-5.
Increased formation of the beta-amyloid peptide (Abeta) is a central event in the pathogenesis of Alzheimer's disease (AD). High cellular cholesterol load promotes Abeta formation. The ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux from cells. We hypothesized that genetic variability in ABCA1 may influence cholesterol metabolism in the central nervous system (CNS) and, thus, interfere with the development of AD. Healthy elderly carriers of the A allele of a non-synonymous (R219K) single nucleotide polymorphism (SNP) in the ABCA1 gene (rs2234884) had on average 33% lower total cholesterol in cerebrospinal fluid (CSF) than non-carriers. In 169 patients with late onset, sporadic AD, this allele was associated with delayed age at onset of the disease by 1.7 years on average. Rs2234884 and another non-synonymous SNP (R1587K) in ABCA1 (rs2234886) failed to show significant association with the risk for AD. We conclude that genetic variability of ABCA1 influences the development of AD, possibly by interfering with CNS cholesterol homeostasis.
β-淀粉样肽（Aβ）生成增加是阿尔茨海默病（AD）发病机制中的核心事件。高细胞胆固醇负荷会促进Aβ生成。ATP结合盒转运蛋白A1（ABCA1）介导细胞内胆固醇外流。我们推测，ABCA1的基因变异性可能会影响中枢神经系统（CNS）中的胆固醇代谢，进而干扰AD的发展。ABCA1基因（rs2234884）中一个非同义（R219K）单核苷酸多态性（SNP）的A等位基因的健康老年携带者，其脑脊液（CSF）中的总胆固醇平均比非携带者低33%。在169例晚发性散发性AD患者中，该等位基因与疾病发病年龄平均延迟1.7年有关。ABCA1中的rs2234884和另一个非同义SNP（R1587K）（rs2234886）与AD风险未显示出显著关联。我们得出结论，ABCA1的基因变异性可能通过干扰CNS胆固醇稳态来影响AD的发展。
