Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Sciences, Shanghai, China.
Graduate School of Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Mol Psychiatry. 2018 Mar;23(3):767-776. doi: 10.1038/mp.2017.136. Epub 2017 Jul 11.
Transient receptor potential canonical 6 (TRPC6) inhibits β-amyloid (Aβ) production. Hyperforin, the TRPC6 agonist, reduces Aβ levels and improves cognitive performance in Alzheimer's disease (AD) models. However, it's unknown whether TRPC6 expression is changed in AD patients. In this case-control study, we measured TRPC6 expression levels in the peripheral blood cells of four independent AD sets from five hospitals and one mild cognitive impairment (MCI) set from a local community (229 AD, 70 MCI, 40 Parkinson disease and 359 controls from China, total n=698) using quantitative real-time PCR assay. We found a specific reduction of TRPC6 mRNA levels in four AD sets and one MCI set. The median TRPC6 mRNA levels were lower in the following: (1) combined AD patients than in age-matched controls (0.78 vs 1.73, P<0.001); (2) mild-to-moderate AD patients than in age-matched controls (0.81 vs 1.73, P<0.001); and (3) MCI patients than in age-matched controls (0.76 vs 1.72, P<0.001). In the receiver-operating characteristic curve analysis, the area under curve was 0.85 for combined AD, 0.84 for mild-to-moderate AD and 0.79 for MCI. In a subgroup of AD patients with brain Aβ examination, TRPC6 was associated with standardized uptake value ratio of Pittsburgh Compound B (Spearman's r=-0.49, P=0.04) and cerebrospinal fluid Aβ42 (Spearman's r=0.43, P=0.04). The TRPC6 reduction in AD patients was further confirmed in blood RNA samples from The Australian Imaging, Biomarkers and Lifestyle Flagship Study of Aging, in post-mortem brain tissues from The Netherlands Brain Bank and in induced pluripotent stem cells-derived neurons from Chinese donors. We conclude that TRPC6 mRNA levels in the blood cells are specifically reduced in AD and MCI patients, and TRPC6 might be a biomarker for the early diagnosis of AD.
瞬时受体电位经典型 6（TRPC6）抑制β-淀粉样蛋白（Aβ）的产生。TRPC6 激动剂贯叶金丝桃素可降低 AD 模型中的 Aβ水平并改善认知表现。然而，AD 患者的 TRPC6 表达是否改变尚不清楚。在这项病例对照研究中，我们使用定量实时 PCR 检测了来自五家医院的四个独立 AD 组和一个来自当地社区的轻度认知障碍（MCI）组的外周血单个核细胞中的 TRPC6 表达水平（中国 229 例 AD、70 例 MCI、40 例帕金森病和 359 例对照，总 n=698）。我们发现四个 AD 组和一个 MCI 组的 TRPC6 mRNA 水平存在特异性降低。以下情况的 TRPC6 mRNA 水平较低：（1）合并 AD 患者与年龄匹配的对照组相比（0.78 比 1.73，P<0.001）；（2）轻度至中度 AD 患者与年龄匹配的对照组相比（0.81 比 1.73，P<0.001）；（3）MCI 患者与年龄匹配的对照组相比（0.76 比 1.72，P<0.001）。在受试者工作特征曲线分析中，联合 AD 的曲线下面积为 0.85，轻度至中度 AD 为 0.84，MCI 为 0.79。在接受脑 Aβ 检查的 AD 患者亚组中，TRPC6 与 Pittsburgh 复合 B 的标准化摄取比值呈负相关（Spearman's r=-0.49，P=0.04）和脑脊液 Aβ42（Spearman's r=0.43，P=0.04）。来自澳大利亚成像、生物标志物和生活方式老龄化旗舰研究的血液 RNA 样本、荷兰脑库的死后脑组织和来自中国供体的诱导多能干细胞衍生神经元进一步证实了 AD 患者的 TRPC6 减少。我们得出结论，AD 和 MCI 患者的血细胞中 TRPC6 mRNA 水平特异性降低，TRPC6 可能是 AD 早期诊断的生物标志物。
