Comparative analysis of amyloid beta deposition in two different Alzheimer’s disease mouse models using whole-brain two-photon microscopy

Abstract

A variety of Alzheimer's disease (AD) mouse models express mutant forms of human amyloid precursor protein (APP), producing high levels of Aβ (Aβ) and forming plaques. However, the degree to which these models mimic spatiotemporal patterns of Aβ deposition in brains of people living with AD is unknown. In this thesis, the spatial distribution of Aβ plaques was mapped across age in two mouse lines (5xFAD, and APPNL−G−F) using in vivo labeling with methoxy-X04, high throughput whole brain imaging, and an automated informatics pipeline. Images were acquired with high resolution serial two-photon tomography and labeled plaques were detected using Ilastik, a semi-automated pixel classification software. Image series were registered to the Allen Mouse Brain Common Coordinate Framework, a 3D reference atlas, enabling automated brain-wide quantification of plaque density, number, and location. In APPNL−G−F mice, plaques were identified first in Isocortex, followed by hippocampal, and cortical subplate areas. In 5xFAD mice, plaque density was highest in hippocampal areas, followed by Isocortex, with little to no involvement of olfactory or cerebellar areas. In summary, this thesis demonstrates that whole-brain imaging of Aβ pathology reveals distinct, model-specific regional patterns of Aβ deposition in 5xFAD and APPNL−G−F mice, highlighting important differences in the spatial distribution and burden of plaques and informing the selection of appropriate models for Alzheimer’s disease research.