Applications of SPR for the characterization of molecules important in the pathogenesis and treatment of neurodegenerative diseases

Abstract

Characterization of binding kinetics and affinity between a potential drug and its receptor are key steps in the development of new drugs. Among the techniques available to determine binding affinities, surface plasmon resonance has emerged as the gold standard because it can measure binding and dissociation rates in real-time in a label-free fashion. Surface plasmon resonance is now finding applications in the characterization of molecules for treatment of neurodegenerative diseases, characterization of molecules associated with pathogenesis of neurodegenerative diseases and detection of neurodegenerative disease biomarkers. In addition it has been used in the characterization of a new class of natural autoantibodies that have therapeutic potential in a number of neurologic diseases. In this review we will introduce surface plasmon resonance and describe some applications of the technique that pertain to neurodegenerative disorders and their treatment.

Keywords::

• Alzheimer’s disease
• amyloid-beta
• antibodies
• biomarkers
• lipid bilayer membrane
• multiple sclerosis
• neuromyelitis optica
• surface modification
• surface plasmon resonance

Acknowledgements

This work was supported by grants from the NIH (R01 GM092993, R01 NS048357 and R21 NS073684) and the National Multiple Sclerosis Society (CA 1060A). This work was also supported by a High-Impact Pilot and Feasibility Award (HIPFA) and Novel Methodology Award (NMDA) from the Mayo Clinic Center for Translational Science Activities (CTSA) and Mayo Clinic CTSA grant number UL1 TR000135 from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH). We also acknowledge with thanks support from the Applebaum, Hilton, Peterson and Sanford Foundations, the Minnesota Partnership Award for Biotechnology and Medical Genomics, the Moon and Marilyn Park Directorship Fund and the McNeilus family.

Financial & competing interests disclosure

M Rodriguez stands to receive royalties for authorship of Multiple Sclerosis (Oxford University Press 2013) and holds the patent for the antibody rHIgM22 licensed to Accorda therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Surface plasmon resonance (SPR) is a label-free optical sensing technique to characterize binding between a soluble ligand and a surface-immobilized receptor.

• Commercial SPR instruments employ a gold film illuminated at an angle to generate surface plasmons. The resonance condition for surface plasmons excitation and subsequent angle of light reflection is very sensitive to the refractive index at the gold–water interface.

• Molecular binding at the gold interface causes an increase in refractive index, which results in a shift in resonance angle and a change in the SPR signal. Monitoring this change as a function of time allows the calculation of association and dissociation rate constants, which in turn can be used to determine affinity for the binding interaction.

• IgM antibodies that bind oligodendrocytes can promote remyelination. Two of these antibodies, mouse IgM O1 and O4, bind lipids that have been incorporated into nanohole array-based SPR sensors. SPR experiments determined that O1 and O4 have much greater affinity for their antigens than do other similar IgMs. Similar human antibodies made in a recombinant form are already in clinical trials for promoting CNS remyelination.

• Pathological IgGs against aquaporin-4 cause cytotoxicity associated with neuromyelitis optica. Small-molecule and antibody inhibitors are being engineered to prevent pathological IgG binding. Characterization of antibody inhibitors by SPR and complimentary methods has identified an antibody with high affinity for aquaporin-4 that blocks binding of pathological IgGs.

• Amyloid fibrilization associated with Alzheimer’s disease can be characterized by SPR.

• SPR can be used for sensitive, specific detection of biomarkers for neurodegenerative diseases like multiple sclerosis and Alzheimer’s disease.

• SPR has the potential to differentiate dementias with specific protein accumulation in neurons (i.e., β-amyloid, tau, α-synuclein, TDP-43, FTDP-17, and so on).

Notes