Classification of human tauopathy using blood: Detection of tau isoforms in patients’ blood with a magnetic bead-based gap sensor

Abstract

Background: Tau protein, which is deposited or phosphorylated in the brains of patients with neurodegenerative progression, has six isoforms that include or exclude N-terminal exons 2 and 3 and Exon 10, which is a microtubule binding region. Especially, 3R- and 4R-tau, which are distinguished by inclusion or exclusion of exon 10, are known to be balanced in normal adults. However, in case of tauopathy such as progressive supranuclear palsy, the balance is disrupted and 4R-tau becomes dominant in the patient’s brain. In this regard, some tauopathies can be classified through comparison of tau isoforms in the blood or cerebrospinal fluid (CSF) of neurodegenerative patients. Method: First, magnetic beads were coated with each antibody that specifically interact with 3R- or 4R-tau protein, respectively. The prepared samples were reacted with patient’s blood samples from 1) healthy control (HC), 2) Alzheimer’s disease (AD), and 3) 4R-tau dominant tauopathy (4RDT). Samples incubated with 3R- and 4R-tau antibodies, respectively, were placed between two metal electrode arrays surrounded by the SU-8 well structure and their impedance changes were measured by electrochemical method (Figure 1). Result: In the case of HC and AD, 3R- and 4R-tau are known to be in balance, but as a result of measuring the impedance change rate, it was found that the impedance change rate of 4R-tau is larger than that of 3R-tau. For the 4R-tau, HC group exhibits a larger impedance change rate than the AD group (Figure 2). The 4RDT group is currently measuring. Based on reference (Acta Neuropathol., 131, 267 (2016)), the impedance change rate of 4R tau in blood will be large, while that of 3R tau is expected to be negligible. Conclusion: We used a magnetic bead-based gap sensor to detect/compare tau isoforms in blood samples collected from living patients. Although slightly different from the expectation, the HC group showed a larger impedance change rate than the AD group for the 4R-tau. The 4RDT group data have not yet been included, but are expected to be similar to those from CSF, and blood measurements can be used to classify tauopathies.