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

Alzheimers disease is a progressive, neurodegenerative condition for which there is no cure. Prominent hypotheses posit that accumulation of beta-amyloid (A{beta}) 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 A{beta} deposition in a mouse model of amyloidosis. We report that structures connected by the fornix show primary susceptibility to A{beta} accumulation and demonstrate that aggregates develop in increasingly complex networks with age. Notably, the densest early A{beta} aggregates occur in the mammillary body coincident with electrophysiological alterations. In later stages, the fornix itself also develops overt A{beta} burden. Finally, we confirm A{beta} in the mammillary body of postmortem patient specimens. Together, our data suggest that subcortical memory structures are particularly vulnerable to A{beta} deposition and that functional alterations within and physical propagation from these regions may underlie the affliction of increasingly complex networks.\n\nAuthor ContributionsRGC, KC, L-HT, ID conceived of the work and planned the experiments.\n\nRGC, HC, JW, LAW, CGY, FA, SMB performed experiments and analyzed data.\n\nHC built the custom microscope.\n\nRGC, L-HT, KC, ID wrote the manuscript.