A transistor-based label-free immunosensor for rapid detection of tau protein

Tau protein in cerebrospinal fluid (CSF) is a central and relevant biomarker of Alzheimer's disease (AD) that correlates with the severity of dementia. Unfortunately, so far, direct label-free detection of tau remains a challenge. Here, we present a transistor-based biosensor that detects the net charge of tau protein directly under physiological conditions. To achieve this, readily available whole anti-tau IgG antibodies are co-immobilized on the sensor surface with polyethylene glycol (PEG) molecules of different molecular weight. We show that by increasing the PEG size from 10 kDa to 20 kDa, the electrical response upon binding of tau improves significantly. These results support recent theoretical work that predicted larger PEGs to form a thicker surface layer with a higher detectable analyte charge. With 20 kDa PEG, we demonstrate label-free tau detection in a wide concentration range with detection limits <1 pM in 150 mM buffer and cell culture media, as well as < 10 pM in artificial CSF. This purely electrical method allows fast and simple tau detection within 30 min without sample processing, washing steps, or labeled detection antibodies. By exchanging the capture antibody, the platform is also amenable to different biomarkers and may enable future diagnostic tools for AD and other diseases.