Rapid, Quantitative Therapeutic Screening for Alzheimer's Enzymes Enabled by Optimal Signal Transduction with Transistors

TL;DR

This study demonstrates that optimized commercially sourced nFETs significantly improve pH sensing resolution, enabling rapid, quantitative measurement of enzyme activity related to Alzheimer's disease and facilitating therapeutic screening.

Contribution

The paper introduces a simple method to enhance nFET pH sensing resolution under closed loop control, enabling effective enzyme activity measurement and drug screening for Alzheimer's disease.

Findings

nFETs achieved ~3-fold better pH resolution than open loop operation.

nFETs' pH resolution was comparable to advanced dg2DFETs.

Demonstrated therapeutic agent p5 restores Cdk5 function.

Abstract

We show that simple, commercially sourced n-channel silicon field-effect transistors (nFETs) operating under closed loop control exhibit an ~3-fold improvement in pH readout resolution to (7.2+/-0.3)x10^-3 at a bandwidth of 10 Hz when compared with the open loop operation commonly employed by integrated ion-sensitive field-effect transistors (ISFETs). We leveraged the improved nFET performance to measure the change in solution pH arising from the activity of a pathological form of the kinase Cdk5, an enzyme implicated in Alzheimer's disease, and showed quantitative agreement with previous measurements. The improved pH resolution was realized while the devices were operated in a remote sensing configuration with the pH sensing element off-chip and connected electrically to the FET gate terminal. We compared these results with those measured by using a custom-built dual-gate 2D field-effect transistor (dg2DFET) fabricated with 2D semi-conducting MoS2 channels and a moderate device gain, alpha=8. Under identical solution conditions the pH resolution of the nFETs was only 2-fold worse than the dg2DFETs pH resolution of (3.9+/-0.7)x10^-3. Finally, using the nFETs, we demonstrated the effectiveness of a custom polypeptide, p5, as a therapeutic agent in restoring the function of Cdk5. We expect that the straight-forward modifications to commercially sourced nFETs demonstrated here will lower the barrier to widespread adoption of these remote-gate devices and enable sensitive bioanalytical measurements for high throughput screening in drug discovery and precision medicine applications.