Neurology Service and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Marqués de Valdecilla University Hospital-University of Cantabria, Santander, Spain.
Neurobiol Aging. 2011 Mar;32(3):547.e1-6. doi: 10.1016/j.neurobiolaging.2009.07.004. Epub 2009 Aug 6.
The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-inducible transcription factor that suppresses microglial inflammatory responses and inhibits amyloid beta (Aβ) production through promoting cholesterol efflux from glial cells. PPAR-γ agonists have been advanced as a new disease altering approach to Alzheimer's disease (AD), with rosiglitazone therapy having improved cognition in those AD patients that did not possess an Apolipoprotein E (APOE) ε4 allele. The current study was designed to explore the effect of interactions between PPAR-γ and APOE gene polymorphisms on the AD risk. We examined genetic variations of PPAR-γ by genotyping 7 haplotype tagging SNPs (htSNPs) (rs10510412, rs17793951, rs1801282, rs4135263, rs1151999, rs709149, and rs709154) in a group of 352 Spanish late-onset AD cases and 438 controls. The PPAR-γ TCCA haplotype derived from SNPs in introns 4 (rs4135263), 5 (rs1151999), and 6 (rs709149 and rs709154) showed a strong protective effect against AD in APOE ε4 allele noncarriers (p=0.001, permutation p=0.006, Bonferroni corrected p=0.021), with a frequency of 39% in cases and 50% in controls. Our data suggest that PPAR-γ genetic variants may modify the risk of AD in an APOE ε4 allele-dependent fashion.
过氧化物酶体增殖物激活受体-γ（PPAR-γ）是一种配体诱导型转录因子，通过促进神经胶质细胞中的胆固醇流出，抑制小胶质细胞的炎症反应并抑制淀粉样蛋白β（Aβ）的产生。PPAR-γ激动剂已被提出作为治疗阿尔茨海默病（AD）的新的疾病改变方法，罗格列酮治疗改善了那些不携带载脂蛋白 E（APOE）ε4等位基因的 AD 患者的认知功能。本研究旨在探讨 PPAR-γ 与 APOE 基因多态性之间的相互作用对 AD 风险的影响。我们通过对 7 个单倍型标签 SNP（htSNP）（rs10510412、rs17793951、rs1801282、rs4135263、rs1151999、rs709149 和 rs709154）进行基因分型，研究了 PPAR-γ 的遗传变异，在一组 352 名西班牙迟发性 AD 病例和 438 名对照中。来自内含子 4（rs4135263）、5（rs1151999）和 6（rs709149 和 rs709154）中的 SNP 的 PPAR-γ TCCA 单倍型在不携带 APOE ε4 等位基因的个体中对 AD 具有很强的保护作用（p=0.001，置换检验 p=0.006，Bonferroni 校正后 p=0.021），病例中的频率为 39%，对照中的频率为 50%。我们的数据表明，PPAR-γ 遗传变异可能以 APOE ε4 等位基因依赖的方式修饰 AD 的风险。
