Tau levels in platelets isolated from Huntington's disease patients serve as a biomarker of disease severity

Abstract

Tau is a microtubule protein that is known to be hyperphosphorylated and to aggregate in several chronic neurodegenerative disorders. In many cases, in particular in Alzheimer's disease, the degree of tau pathology has been demonstrated to correlate with cognitive deficits and/or decline. In Huntington's disease (HD), a dominantly inherited neurodegenerative disorder, both cognitive impairments and abnormal tau expression have been reported to occur, along with the accumulation of the mutant huntingtin protein. In this respect, tau has been shown to be present in the cerebrospinal fluid of individuals with HD and to increase with disease progression. However, how this relates to changes in tau found in the periphery is largely unknown. In this study, we collected blood samples from patients with HD and isolated multiple blood components including plasma, platelets, and peripheral blood mononuclear cells to measure their tau levels and subsequently correlate these to cognitive impairments and disease stage. Our results suggest that the amount of tau, particularly N-terminal tau (NTA-tau) and total tau (t-tau), is elevated in all assayed blood components and that the quantity of tau within platelets, specifically, is strongly correlated with disease severity.

Keywords: Blood; Cognition; NTA-tau; PBMC; Phosphorylated tau; Plasma.

Fig. 1

Plasma levels of NTA-tau, p-tau 181, and p-tau 231 increase with disease stage in HD patients. NTA-tau, p-tau 181, and p-tau 231 levels in plasma were all measured by Simoa. Total cohort n = 64 CTRL, 55 manifest HD, 13 pHD. Stages 3–5 n = 17 CTRL, 17 manifest HD. Statistical analyses were performed using a one-way ANOVA for comparison between CTRL, HD patients and pHD gene carriers, a Spearman test for all correlations and a Student’s unpaired t test for CTRL and stage 3–5 HD patients. * p < 0.05. One way ANOVA results: NTA-Tau between controls, manifest HD and pHD: (F(2,115) = 3.855, p = 0.0240); p-tau 231 between CTRL, manifest HD and pHD (F(2,129) = 0.602, p = 0.5464); p-tau 181 between controls, manifest HD and pHD (F(2,128) = 1.126, p = 0.3274). CTRL control, HD Huntington’s disease, MMSE mini mental state examination, NTA-tau N-terminal tau, pHD premanifest gene carriers, p-tau 181 tau phosphorylated at residue 181, p-tau 231 tau phosphorylated at residue 231, TFC total functional capacity

Fig. 2

Total tau is increased in PBMC isolated from HD patients. Levels p-tau and total tau were evaluated by western blot. Total cohort n = 45 CTRL, 43 HD, 9 pHD. Patients and premanifest gene carriers were pooled in all graphs as no effect of stage was observed. Statistics were performed using a Student’s unpaired t test, or, where variances were unequal, a Kruskal–Wallis test, for comparisons of CTRL to HD gene carriers. Correlations were evaluated using a Spearman test. Spearman’s rho and p values are reported on each graph or in the summary table. * p < 0.05. ACE-R Addenbrooke’s cognitive exam revised, cUHDRS composite unified HD rating scale score, DBS disease burden score, HD Huntington’s disease, kDa kilodalton, MMSE Mini-Mental State Examination, pS199 tau phophorylated at serine residue 199, TFC total functional capacity, WBC white blood cell. + ve, positive control; -ve, negative control

Fig. 3

Total tau levels are increased in HD patients and strongly correlate with disease stage and clinical features. Levels of p-tau 199 and t-tau were evaluated by western blot. Total cohort n = 29 CTRL, 26 HD, 9 pHD. Graphs below the representative immunoblot include only CTRL and manifest HD patients as a significant correlation between disease stage and t-tau levels was present. Both manifest and premanifest gene carriers are included in all correlation analyses. Levels of t-tau in platelets significantly correlated with disease stage and TFC. Statistics were performed using a Student’s unpaired t test for comparison of CTRL to manifest HD patients. Correlations were evaluated using a Spearman test. * p < 0.05. ACE-R Addenbrooke’s cognitive examination revised, cUHDRS composite unified HD rating scale, DBS disease burden score, HD Huntington’s disease, kDa kilodalton, MMSE Mini-Mental State Examination, pS199 tau phosphorylated at serine residue 199, TFC total functional capacity