ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer’s disease
ABCA1 modulates CSF cholesterol levels and influences the age at onset of Alzheimer’s disease
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DOI：
10.1016/s0197-4580(02)00094-5
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发表时间：
2003-05
影响因子：
4.2
通讯作者：
M. Wollmer;J. Streffer;D. Lütjohann;M. Tsolaki;Vassiliki Iakovidou;T. Hegi;T. Pasch;H. Jung;K. Bergmann;R. Nitsch;C. Hock;A. Papassotiropoulos
中科院分区：
文献类型：
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作者：
M. Wollmer;J. Streffer;D. Lütjohann;M. Tsolaki;Vassiliki Iakovidou;T. Hegi;T. Pasch;H. Jung;K. Bergmann;R. Nitsch;C. Hock;A. Papassotiropoulos
β-淀粉样肽 (Aβ) 形成的增加是阿尔茨海默病 (AD) 发病机制中的一个核心事件。高细胞胆固醇负荷促进 Aβ 形成。 ATP 结合盒转运蛋白 A1 (ABCA1) 介导胆固醇从细胞流出。我们假设 ABCA1 的遗传变异可能影响中枢神经系统 (CNS) 中的胆固醇代谢，从而干扰 AD 的发展。 ABCA1 基因 (rs2234884) 中非同义 (R219K) 单核苷酸多态性 (SNP) A 等位基因 (SNP) 的健康老年携带者脑脊液 (CSF) 中的总胆固醇平均比非携带者低 33%。在 169 名晚发、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 年相关。 Rs2234884 和 ABCA1 (rs2234886) 中的另一个非同义 SNP (R1587K) 未能显示与 AD 风险显着相关。我们得出结论，ABCA1 的遗传变异可能通过干扰 CNS 胆固醇稳态来影响 AD 的发展。
Increased formation of the β-amyloid peptide (Aβ) is a central event in the pathogenesis of Alzheimer’s disease (AD). High cellular cholesterol load promotes Aβ 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.