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• W3119248879 abstract "Abstract Genetic and biochemical evidence implicates 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 mapped the regiospecificity of various anti-Aβ treatments by high-resolution light-sheet imaging of amyloid plaques in electrophoretically clarified brains of Thy1-APP mice overexpressing Aβ. We found that Aβ plaques in whole brains progressed from 1.2*10 6 to 2.5*10 6 (standard deviation ± 1.6*10 5 and ± 4.3*10 5 respectively) over a 9-month period. We then assessed the regiospecific plaque clearance in mice subjected to β-secretase inhibition, amyloid intercalation by polythiophenes, or anti-Aβ antibodies. Each treatment showed unique spatiotemporal Aβ clearance signatures, with polythiophenes emerging as potent anti-Aβ compounds with promising pharmacokinetic properties. We then interrogated genes matching regiospecific Aβ clearance by aligning voxels that showed drug effectiveness to spatial-transcriptomics atlases. Bace1 and Thy1 expression matched the regiospecific efficacy of BACE inhibition, confirming the validity of our analyses. Voxels cleared by polythiophenes correlated with transcripts encoding synaptic proteins, whereas voxels cleared by BACE inhibition correlated with oligodendrocyte-specific genes. The restricted regional susceptibility of Aβ plaques to specific treatments may contribute to the clinical failure of anti-Aβ therapies. The striking regiospecificity of the treatments studied suggests that combinatorial regimens may improve functional outcomes. One sentence summary 3D microscopy of Aβ plaques reveals that Alzheimer’s disease therapeutics have regiospecific effects that can be mapped to distinct genetic networks." @default.
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• W3119248879 date "2021-01-15" @default.
• W3119248879 modified "2023-10-18" @default.
• W3119248879 title "Local predictors of anti-Aβ therapy efficacy revealed by quantitative whole-brain microscopy" @default.
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