Reduced TRPC6 mRNA levels in the blood cells of patients with Alzheimer's disease and mild cognitive impairment

Transient receptor potential canonical 6 (TRPC6) inhibits beta-amyloid (A beta) production. Hyperforin, the TRPC6 agonist, reduces A beta 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, Po0.001); (2) mild-to-moderate AD patients than in age-matched controls (0.81 vs 1.73, Po0.001); and (3) MCI patients than in age-matched controls (0.76 vs 1.72, Po0.001). 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 A beta examination, TRPC6 was associated with standardized uptake value ratio of Pittsburgh Compound B (Spearman's r = -0.49, P = 0.04) and cerebrospinal fluid A beta 42 (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.