Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease

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Abstract

One way to image the molecular pathology in Alzheimer's disease is by positron emission tomography using probes that target amyloid fibrils. However, these fibrils are not closely linked to the development of the disease. It is now thought that early-stage biomarkers that instigate memory loss are composed of Aβ oligomers. Here, we report a sensitive molecular magnetic resonance imaging contrast probe that is specific for Aβ oligomers. We attach oligomer-specific antibodies onto magnetic nanostructures and show that the complex is stable and binds to Aβ oligomers on cells and brain tissues to give a magnetic resonance imaging signal. When intranasally administered to an Alzheimer's disease mouse model, the probe readily reached hippocampal Aβ oligomers. In isolated samples of human brain tissue, we observed a magnetic resonance imaging signal that distinguished Alzheimer's disease from controls. Such nanostructures that target neurotoxic Aβ oligomers are potentially useful for evaluating the efficacy of new drugs and ultimately for early-stage Alzheimer's disease diagnosis and disease management.

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Figure 1: Aβ oligomers (AβOs) bind to neuronal surfaces in a saturable, receptor-mediated manner and are distinct from amyloid plaques.
Figure 2: Individual components of the NU4MNS probe.
Figure 3: NU4MNS attachment to hippocampal neurons is specific to AβOs.
Figure 4: NU4 and NU4MNS discriminate Alzheimer's disease human frontal cortex sections from aged controls.
Figure 5: NU4 antibody detects dendrite-bound AβOs in fixed tissue and binds its target within 4 h following intranasal inoculation.
Figure 6: NU4MNS labelling of human and Tg mouse brain slices gives a pronounced, Alzheimer's disease-dependent MRI signal that is confirmed in vivo.

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Acknowledgements

The authors thank the staff of the Biological Imaging Facility (BIF), the Center for Advanced Molecular Imaging (CAMI) and Northwestern University's Atomic and Nanoscale Characterization Experimental Center (NUANCE) at Northwestern University, and the Department of Radiology at NorthShore University HealthSystems. The authors also thank the Northwestern Brain Bank at the Cognitive Neurology and Alzheimer's Disease Center (CNADC) for providing the human Alzheimer's disease and control brain tissue. The authors acknowledge support from their funding agencies and grants. This work was funded by the National Institutes of Health (AG022547, AG029460 and AG045637 to W.L.K.), by Baxter Healthcare (to W.L.K.) and partially by the National Institutes of Health–Centers of Cancer Nanotechnology Excellence through the Nanoconstruct Core (award U54CA119341 to V.P.D., H.J. and M.D.)

Author information

The study concept and design was provided by K.L.V., J.S., R.S., M.D., V.P.D. and W.L.K. The acquisition of data was performed by M.D., H.J., J.S. and S.V. (MNS development, production, and characterization), K.L.V., J.S., R.S., M.A.B., J.W., S.V., S.S., S.W., C.L. and J.P. (antibody conjugation, cell experiments, tissue experiments and immunoprecipitation experiments), K.L.V. and M.A.B. (animal experiments), K.M. (inductively coupled plasma mass spectrometry experiments) and E.A.W. and P.P (magnetic resonance image acquisition). All authors discussed the results and contributed to the analysis of the data. Critical revision of the article for intellectual content was conducted by K.L.V., J.S., R.S., M.D., P.T.V., V.P.D. and W.L.K. Funding was obtained and studies supervised by W.L.K. and V.P.D.

Correspondence to Vinayak P. Dravid or William L. Klein.

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Competing interests

This work was funded, in part, by Baxter Healthcare. Northwestern University holds the rights to two US and several international patents concerning antibodies that target Aβ oligomer assemblies. Acumen Pharmaceuticals holds the licensing rights to develop anti-Aβ oligomer antibodies for therapeutic use.

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Viola, K., Sbarboro, J., Sureka, R. et al. Towards non-invasive diagnostic imaging of early-stage Alzheimer's disease. Nature Nanotech 10, 91–98 (2015). https://doi.org/10.1038/nnano.2014.254

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