Longitudinal quantitative whole-brain microscopy reveals distinct temporal and spatial efficacies of anti-Aβ therapies
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.
Helmchen Fritjof、Trevisan Chiara、Kirschenbaum Daniel、Catto Francesca、Lee Jin Hyung、Dadgar-Kiani Ehsan、Voigt Fabian F.、Bichsel Oliver、Aguzzi Adriano、Shirani Hamid、Nilsson K. Peter R.、Paganetti Paolo、Frontzek Karl Joachim
Laboratory of Neural Circuit Dynamics, Brain Research InstituteInstitute of Neuropathology, University Hospital Zurich, University of ZurichInstitute of Neuropathology, University Hospital Zurich, University of ZurichInstitute of Neuropathology, University Hospital Zurich, University of ZurichDepartment of Bioengineering, Stanford University||Department of Neurology and Neurological Sciences, Stanford University||Department of Electrical Engineering, Stanford University||Department of Neurosurgery, Stanford UniversityDepartment of Bioengineering, Stanford UniversityLaboratory of Neural Circuit Dynamics, Brain Research Institute||Neuroscience Center Zurich, University of Zurich & ETH ZurichInstitute of Neuropathology, University Hospital Zurich, University of ZurichInstitute of Neuropathology, University Hospital Zurich, University of ZurichDepartment of Physics, Chemistry and Biology, Division of Chemistry, Link?ping UniversityDepartment of Physics, Chemistry and Biology, Division of Chemistry, Link?ping UniversityLaboratory for Biomedical Neurosciences, Neurocenter of Southern Switzerland, Ente Cantonale Ospedaliero||Faculty of Biomedical Neurosciences, Universit¨¤ della Svizzera ItalianaInstitute of Neuropathology, University Hospital Zurich, University of Zurich
基础医学神经病学、精神病学生物科学研究方法、生物科学研究技术
Helmchen Fritjof,Trevisan Chiara,Kirschenbaum Daniel,Catto Francesca,Lee Jin Hyung,Dadgar-Kiani Ehsan,Voigt Fabian F.,Bichsel Oliver,Aguzzi Adriano,Shirani Hamid,Nilsson K. Peter R.,Paganetti Paolo,Frontzek Karl Joachim.Longitudinal quantitative whole-brain microscopy reveals distinct temporal and spatial efficacies of anti-Aβ therapies[EB/OL].(2025-03-28)[2025-06-03].https://www.biorxiv.org/content/10.1101/2021.01.15.426090.点此复制
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