Three-dimensional quantitative analysis of amyloid plaques in the whole brain with high voxel resolution

Amyloidosis of the central nervous system is one of the main pathological hallmarks of Alzheimer’s disease (AD). Changes in the number and the load of amyloid plaque (Aβ) deposition are important indicators of the progression of AD. However, the quantitative analysis of amyloidosis at the subcellular level in the whole brain remains a substantial challenge. In this study, an automatic analysis method was established for assessing amyloid plaques in the whole brain, including convenient whole brain labeling, imaging with a fluorescence micro-optical sectioning tomography system (fMOST) and an automated three-dimensional (3D) analysis method. Validation using immunostaining showed that the detection rate of amyloid plaques larger than 10 µm was 97.71%±0.18%. We achieved a 3D dataset of amyloid plaques in the whole brain of a 5XFAD transgenic mouse at a resolution of 0.32 μm×0.32 μm×2 μm and quantitatively analyzed the 3D distribution of amyloid plaques in different brain regions and nuclei through automated registration, segmentation and counting. The results indicated that the combination of the fMOST system with a whole brain staining method enables the acquisition and quantitative analysis of a brain-wide dataset of amyloid plaques, which may contribute to elucidating the underlying pathogenesis of AD and therapeutic drug discovery.