Longitudinal quantitative whole-brain microscopy reveals distinct temporal and spatial efficacies of anti-Aβ therapies

Abstract

Many efforts targeting amyloid-β (Aβ) plaques for the treatment of Alzheimer's Disease thus far have resulted in failures during clinical trials. Regional and temporal heterogeneity of efficacy and dependence on plaque maturity may have contributed to these disappointing outcomes. In this study, we mapped the regional and temporal specificity of various anti-Aβ treatments through high-resolution light-sheet imaging of electrophoretically-cleared brains. We assessed the effect on amyloid plaque formation and growth in Thy1-APP/PS1 mice subjected to β-secretase inhibitors, polythiophenes, or anti-Aβ antibodies. Each treatment showed unique spatiotemporal Aβ clearance, with polythiophenes emerging as a potent anti-Aβ compound. Furthermore, aligning with a spatial-transcriptomic atlas revealed transcripts that correlate with the efficacy of each Aβ therapy. As observed in this study, there is a striking dependence of specific treatments on the location and maturity of Aβ plaques. This may also contribute to the clinical trial failures of Aβ-therapies, suggesting that combinatorial regimens may be significantly more effective in clearing amyloid deposition.

Competing Interest Statement

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

Footnotes

* We reduced the emphasis on the spatial transcriptomic data, while including more data about the therapeutic effects of the drugs we tested. We improved the quality of figures and included additional validation for the analytical pipeline.

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

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