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.

中文翻译：

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纵向定量全脑显微镜显示抗 Aβ 疗法的不同时间和空间功效

迄今为止，许多针对淀粉样蛋白-β (Aβ) 斑块治疗阿尔茨海默病的努力都导致临床试验失败。疗效的区域和时间异质性以及对斑块成熟度的依赖可能导致了这些令人失望的结果。在这项研究中，我们通过电泳清除大脑的高分辨率光片成像绘制了各种抗 Aβ 治疗的区域和时间特异性。我们评估了接受 β-分泌酶抑制剂、聚噻吩或抗 Aβ 抗体的 Thy1-APP/PS1 小鼠对淀粉样斑块形成和生长的影响。每种处理都显示出独特的时空 Aβ 清除率，聚噻吩作为一种有效的抗 Aβ 化合物出现。此外，与空间转录组图谱对齐，揭示了与每种 Aβ 疗法的功效相关的转录本。正如本研究中所观察到的，特定治疗对 Aβ 斑块的位置和成熟度有着显着的依赖性。这也可能导致 Aβ 疗法的临床试验失败，这表明组合方案在清除淀粉样蛋白沉积方面可能更有效。