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.
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This work was partially supported by the grants from the National Key Research and Development Program Foundation of China (2016YFC1306400), and from the Origincell Technology Group Co. Ltd, China. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. RL and JFW did the experiments and wrote the manuscript. YMS, HLL, YG, WZ, YJW, SDC, CJZ and ZYW made diagnosis of patients and collected clinical samples. JW, CJF, QXL and CLM did the experiments with the AIBL samples. RT and NHJ did establishment and induction of iPSCs. TZ repeated some experiments. RL and JFW analyzed the data. YZW supervised the project and wrote the manuscript. RL and YZW have full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
A Chinese patent application entitled ‘Methods for early diagnosis of Alzheimer’s disease by the measurement of TRPC6 mRNA levels in the peripheral blood cells’ (201410035943.8) was filed on 24 January 2014. RL, JW and YW are the inventors. The applicant is Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. A PCT patent application entitled ‘Methods for early diagnosis of Alzheimer’s disease by the measurement of TRPC6 mRNA levels in the peripheral blood cells’ (PCT/CN2014/071325) was filed on 24 January 2014. RL, JW and YW are the inventors. The applicant is Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All other authors declare that there are no conflicts of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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