Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
J Neural Transm (Vienna). 2012 Jul;119(7):833-42. doi: 10.1007/s00702-012-0823-x. Epub 2012 May 25.
Alzheimer's disease (AD) is the most common neurodegenerative disease, and is clinically characterized by cognitive disturbances and the accumulation of the amyloid β (Aβ) peptides in plaques in the brain. Recent studies have shown the links between AD and the immediate-early gene Arc (activity-regulated cytoskeleton-associated protein), involved in synaptic plasticity and memory consolidation. For example, AD mouse models show a decreased expression of Arc mRNA in the brain. In additional, acute Aβ application to brain slices leads to a widespread ARC protein diffusion, unlike the normal defined localization to synapses. In this study, we investigated genetic variation in human ARC and the risk of developing AD. To this end, we genotyped 713 subjects diagnosed with AD and 841 controls without dementia. ARC was sequenced in a group of healthy individuals, and seven previously known SNPs and three novel SNPs were identified. Two of the newly found SNPs were intronic and one, +2852(G/A), was located in the 3'UTR. Three tag SNPs were selected, including the novel SNP +2852(G/A), to relate to risk of AD, Mini Mental State Examination (MMSE) scores and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau181 (P-tau(181)) and Aβ(1-42). The AA genotype of the newly found 3'-UTR SNP +2852(A/G), was associated with a decreased risk of AD (p (c) = 0.005; OR = 0.74; 95 % CI: 0.61-0.89). No associations of single SNPs or haplotypes with MMSE score or CSF biomarkers were found. Here we report a novel ARC SNP associated with a reduced risk of developing AD. To our knowledge, this is the first study associating a gene variant of ARC with any disease. The location of the SNP within the 3'UTR indicates that dendritic targeting of ARC mRNA could be involved in the molecular mechanisms underlying this protective function. However, further investigation of the importance of this SNP for ARC function, ARC processing and the pathology of AD is needed.
阿尔茨海默病（AD）是最常见的神经退行性疾病，其临床特征是认知障碍和大脑斑块中淀粉样β（Aβ）肽的积累。最近的研究表明 AD 与即时早期基因 Arc（活性调节细胞骨架相关蛋白）之间存在联系，Arc 参与突触可塑性和记忆巩固。例如，AD 小鼠模型显示大脑中 Arc mRNA 的表达降低。此外，急性 Aβ 应用于脑片会导致广泛的 ARC 蛋白扩散，与正常的突触定位不同。在这项研究中，我们研究了人类 ARC 的遗传变异与 AD 发病风险之间的关系。为此，我们对 713 名被诊断患有 AD 的患者和 841 名无痴呆症的对照者进行了基因分型。在一组健康个体中对 ARC 进行了测序，并发现了 7 个先前已知的 SNP 和 3 个新的 SNP。其中 2 个新发现的 SNP 位于内含子中，1 个位于 +2852（G/A），位于 3'UTR 中。选择了 3 个标记 SNP，包括新发现的 +2852（G/A），以与 AD 风险、简易精神状态检查（MMSE）评分和脑脊液（CSF）总 tau（T-tau）、过度磷酸化 tau181（P-tau(181)) 和 Aβ(1-42) 的生物标志物水平相关。新发现的 3'UTR SNP +2852（A/G）的 AA 基因型与 AD 风险降低相关（p (c) = 0.005；OR = 0.74；95%CI：0.61-0.89）。未发现单个 SNP 或单倍型与 MMSE 评分或 CSF 生物标志物相关。在这里，我们报告了一个与 AD 发病风险降低相关的新的 ARC SNP。据我们所知，这是第一个将 ARC 基因变异与任何疾病相关联的研究。该 SNP 位于 3'UTR 内的位置表明 ARC mRNA 的树突靶向可能参与了这种保护功能的分子机制。然而，需要进一步研究该 SNP 对 ARC 功能、ARC 加工和 AD 病理学的重要性。
