Journal Article

Whole‐brain microscopy reveals distinct temporal and spatial efficacy of anti‐Aβ therapies

Trevisan, Chiara, Kirschenbaum, Daniel, Voigt, Fabian F, Frontzek, Karl J, Nilsson, K Peter R, Aguzzi, Adriano, Catto, Francesca, Paganetti, Paolo, Bichsel, Oliver, Lee, Jin Hyung, Shirani, Hamid, Dadgar‐Kiani, Ehsan, Helmchen, Fritjof

2023

Overview

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. Synopsis The brain is highly compartmentalized with many distinct regions. It is unknown how drugs for treating Alzheimer's Disease (AD) work across brain regions and disease stages. We developed a technology to quantify the effects of different AD drugs throughout the brain at different time points. A novel technology was developed for high‐throughput optical mouse brain clarification and staining of Aβ plaques, followed by lightsheet imaging, brain atlas registration, and plaque morphology quantification. Mice were treated with either a BACE1 inhibitor, a polythiophene for stabilizing amyloid fibrils, or an anti‐Aβ antibody. Quantitative results show distinct Aβ plaque modification and removal across brain regions and disease stage. Spatial efficacy profiles of anti‐Aβ therapies were correlated with gene expression maps using a spatial transcriptomics brain atlas. Graphical Abstract The brain is highly compartmentalized with many distinct regions. It is unknown how drugs for treating Alzheimer's Disease (AD) work across brain regions and disease stages. We developed a technology to quantify the effects of different AD drugs throughout the brain at different time points.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Alzheimer Disease - drug therapy / Alzheimer's disease / Amyloid beta-Peptides - metabolism / Amyloid beta-Protein Precursor / amyloid‐beta / Animals / Antibodies / Brain / Brain - metabolism / Clinical trials / Disease Models, Animal / EMBO22 / EMBO27 / Hydrogels / light‐sheet microscopy / Mice / Mice, Transgenic / Microscopy / Morphology / Neurodegenerative diseases / Neuroimaging / Plaque, Amyloid - drug therapy / Presenilin 1 / Presenilin-1 - pharmacology / Secretase / Senile plaques / Stains & staining / tissue clearing / Transcriptomics / β-Amyloid