Alzheimer’s disease (AD) is a progressive, neurodegenerative dementia with no cure. Prominent hypotheses suggest accumulation of beta-amyloid (Aβ) contributes to neurodegeneration and memory loss, however identifying brain regions with early susceptibility to Aβ remains elusive. Using SWITCH to immunolabel intact brain, we created a spatiotemporal map of Aβ deposition in the 5XFAD mouse. We report that subcortical memory structures show primary susceptibility to Aβ and that aggregates develop in increasingly complex networks with age. The densest early Aβ 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 Aβ in the mammillary body correlates with neuronal hyper-excitability and that modulation using a pharmacogenetic approach reduces Aβ 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.
Bibliographical noteFunding Information:
The authors would like to acknowledge Michiel Kooreman at the Netherlands Brain Bank for help procuring the PPFE human tissue and Teresa Lima for her expert advice in preparing the human PPFE brain tissue for the optimized CLARITY protocol. We would also like to thank Nina Dedic for her advice and helpful comments on the project and paper. In addition, we would like to acknowledge Naveed Bakh, Sung-Yon Kim, and Kamilla Tekiela for helping lay the groundwork for the experiments presented in this work. This work was funded by Ludwig Foundation, NIH grant RF1AG047661 and JPB Foundation Funding (PIIF and PNDRF) to L.-H.T. and by the Norman B. Leventhal and Barbara Weedon fellowships to R.G.C. In addition, K.C. was supported by Burroughs Wellcome Fund Career Awards at the Scientific Interface, the Searle Scholars Program, Packard award in Science and Engineering, NARSAD Young Investigator Award, JPB Foundation (PIIF and PNDRF), NCSOFT Cultural Foundation, and NIH (1-U01-NS090473–01, P30AG10161, and RF1AG15819).
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Agricultural and Biological Sciences(all)
- Medicine (miscellaneous)