ABSTRACT
Alzheimer's disease (AD) is a progressive, neurodegenerative dementia with no cure. Prominent hypotheses suggest accumulation of beta-amyloid (Aß) contributes to neurodegeneration and memory loss, however identifying brain regions with early susceptibility to Aß remains elusive. Using SWITCH to immunolabel intact brain, we created a spatiotemporal map of Aß deposition in the 5XFAD mouse. We report that subcortical memory structures show primary susceptibility to Aß and that aggregates develop in increasingly complex networks with age. The densest early Aß occurs in the mammillary body, septum, and subiculum- core regions of the Papez memory circuit. Previously, early mammillary body dysfunction in AD had not been established. We also show that Aß in the mammillary body correlates with neuronal hyper-excitability and that modulation using a pharmacogenetic approach reduces Aß deposition. Our data demonstrate large-tissue volume processing techniques can enhance biological discovery and suggest that subcortical susceptibility may underlie early brain alterations in AD.