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Quantitative 3D microscopy reveals a genetic network predicting the local activity of anti-Aβ compounds

View ORCID ProfileDaniel Kirschenbaum, View ORCID ProfileFabian F. Voigt, Ehsan Dadgar-Kiani, View ORCID ProfileFrancesca Catto, Chiara Trevisan, View ORCID ProfileOliver Bichsel, Hamid Shirani, K. Peter R. Nilsson, View ORCID ProfileKarl Joachim Frontzek, View ORCID ProfilePaolo Paganetti, View ORCID ProfileFritjof Helmchen, Jin Hyung Lee, View ORCID ProfileAdriano Aguzzi
doi: https://doi.org/10.1101/2021.01.15.426090
Daniel Kirschenbaum
1Institute of Neuropathology, University Hospital Zurich, University of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland
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  • ORCID record for Daniel Kirschenbaum
Fabian F. Voigt
2Laboratory of Neural Circuit Dynamics, Brain Research Institute, University of Zurich Winterthurerstrasse 190, CH-8057 Zurich, Switzerland, Neuroscience Center Zurich, University of Zurich & ETH Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
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Ehsan Dadgar-Kiani
3Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
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Francesca Catto
1Institute of Neuropathology, University Hospital Zurich, University of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland
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Chiara Trevisan
1Institute of Neuropathology, University Hospital Zurich, University of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland
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Oliver Bichsel
1Institute of Neuropathology, University Hospital Zurich, University of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland
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Hamid Shirani
4Department of Physics, Chemistry and Biology, Division of Chemistry, Linköping University, SE-581 83 Linköping, Sweden
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K. Peter R. Nilsson
4Department of Physics, Chemistry and Biology, Division of Chemistry, Linköping University, SE-581 83 Linköping, Sweden
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Karl Joachim Frontzek
1Institute of Neuropathology, University Hospital Zurich, University of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland
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Paolo Paganetti
5Laboratory for Biomedical Neurosciences, Neurocenter of Southern Switzerland, Ente Cantonale Ospedaliero, CH-6807 Torricella-Taverne, Switzerland, Faculty of Biomedical Neurosciences, Università della Svizzera Italiana, CH-6900 Lugano, Switzerland
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Fritjof Helmchen
2Laboratory of Neural Circuit Dynamics, Brain Research Institute, University of Zurich Winterthurerstrasse 190, CH-8057 Zurich, Switzerland, Neuroscience Center Zurich, University of Zurich & ETH Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
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Jin Hyung Lee
3Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
6Neurology and Neurological Sciences, Bioengineering, Neurosurgery, and Electrical Engineering, Stanford University
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  • For correspondence: adriano.aguzzi@usz.ch ljinhy@stanford.edu
Adriano Aguzzi
1Institute of Neuropathology, University Hospital Zurich, University of Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland
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  • ORCID record for Adriano Aguzzi
  • For correspondence: adriano.aguzzi@usz.ch ljinhy@stanford.edu
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Abstract

Genetic and biochemical evidence suggests a role for amyloid-β (Aβ) in Alzheimer’s disease, yet many anti-Aβ treatments are clinically ineffective. Regional heterogeneity of efficacy may contribute to these disappointing results. Here we compared the regiospecificity of various anti-Aβ treatments by combining focused electrophoretic whole-brain clearing, amyloid labelling and light-sheet imaging with whole-brain analyses of plaque topology in Aβ-overexpressing mice. Aβ plaque numbers progressed from around 1’200’000 to 2’500’000 over a 9-month period. We then assessed the regiospecific plaque clearance in mice subjected to β-secretase inhibition, amyloid intercalation by polythiophenes, and anti-Aβ antibodies. Each treatment showed unique spatiotemporal Aβ clearance signatures, with polythiophenes emerging as potent anti-Aβ compounds with promising pharmacokinetic properties and the anti-Aβ antibody showing only minor effects. By aligning (25 μm)3 voxels that showed drug effectiveness to spatial transcriptomics atlases, we identified genes matching regiospecific Aβ clearance. As expected, Bace1 expression was highly correlated with the regiospecific efficacy of BACE inhibition. In addition, we found that voxels cleared by polythiophenes correlated with transcripts encoding synaptic proteins, whereas voxels cleared by BACE inhibition correlated with oligodendrocyte-specific genes. The differential regional susceptibility of distinct plaque populations to specific treatments may explain the clinical failure of anti-Aβ therapies, and suggests that combinatorial regimens may improve functional outcomes.

Competing Interest Statement

J.H.L. is a founder, consultant, and shareholder of LVIS. The University of Zurich has filed a patent pro-tecting certain aspects of the rapid-clarification technology described here.

Footnotes

  • https://github.com/leelabhub/alz-drug-3d/

  • https://grabcad.com/library/electrophoretic-tissue-clearing-and-staining-chamber-1

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted January 15, 2021.
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Quantitative 3D microscopy reveals a genetic network predicting the local activity of anti-Aβ compounds
Daniel Kirschenbaum, Fabian F. Voigt, Ehsan Dadgar-Kiani, Francesca Catto, Chiara Trevisan, Oliver Bichsel, Hamid Shirani, K. Peter R. Nilsson, Karl Joachim Frontzek, Paolo Paganetti, Fritjof Helmchen, Jin Hyung Lee, Adriano Aguzzi
bioRxiv 2021.01.15.426090; doi: https://doi.org/10.1101/2021.01.15.426090
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Quantitative 3D microscopy reveals a genetic network predicting the local activity of anti-Aβ compounds
Daniel Kirschenbaum, Fabian F. Voigt, Ehsan Dadgar-Kiani, Francesca Catto, Chiara Trevisan, Oliver Bichsel, Hamid Shirani, K. Peter R. Nilsson, Karl Joachim Frontzek, Paolo Paganetti, Fritjof Helmchen, Jin Hyung Lee, Adriano Aguzzi
bioRxiv 2021.01.15.426090; doi: https://doi.org/10.1101/2021.01.15.426090

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