3D Mapping Reveals Network-specific Amyloid Progression and Subcortical Susceptibility

Abstract

AbstractAlzheimer’s disease is a progressive, neurodegenerative condition for which there is no cure. Prominent hypotheses posit that accumulation of beta-amyloid (Aβ) peptides drives the neurodegeneration that underlies memory loss, however the spatial origins of the lesions remain elusive. Using SWITCH, we created a spatiotemporal map of Aβ deposition in a mouse model of amyloidosis. We report that structures connected by the fornix show primary susceptibility to Aβ accumulation and demonstrate that aggregates develop in increasingly complex networks with age. Notably, the densest early Aβ aggregates occur in the mammillary body coincident with electrophysiological alterations. In later stages, the fornix itself also develops overt Aβ burden. Finally, we confirm Aβ in the mammillary body of postmortem patient specimens. Together, our data suggest that subcortical memory structures are particularly vulnerable to Aβ deposition and that functional alterations within and physical propagation from these regions may underlie the affliction of increasingly complex networks.Author ContributionsRGC, KC, L-HT, ID conceived of the work and planned the experiments.RGC, HC, JW, LAW, CGY, FA, SMB performed experiments and analyzed data.HC built the custom microscope.RGC, L-HT, KC, ID wrote the manuscript.